The present invention relates to a novel compound, a method for producing the novel compound, a squalene-synthesizing enzyme inhibitor, a cholesterol biosynthesis inhibitor and a triglyceride biosynthesis inhibitor containing such a novel compound and also to a medicinal composition containing them. More specifically, the present invention relates to preventive and curative agents for hyper lipidemia including arterial sclerosis diseases and ischemic heart diseases.
Cholesterol is a sterol which is biosynthesized in all animal cells except for a red blood cell and is a factor essential for maintaining a plasma membrane and for the creation of a steroid hormone. Cholesterol is liposoluble and exists as hypobaric lipoprotein (LDL), hyperbaric lipoprotein (HDL) and the like in blood. LDL in blood is incorporated into cells through an acceptor on the surface of the cells and regenerates free cholesterol after decomposed. This is a major route for incorporating cholesterol from the outside of cells. Also, it has been known that a major enzyme which participates in the biosynthesis of LDL acceptor protein and cholesterol undergoes feedback of the concentration of cholesterol which is the harvested product. In this manner, the level of cholesterol in cells is maintained and controlled exquisitely by the feedback control mechanism of the LDL acceptor and biosynthetic type enzyme on the basis of a balance between the biosynthesis of a cell itself and the incorporation of LDL from the outside of a cell.
In recent years, cholesterol has been recognized as the main culprit of hyper lipidemia and also as the most dangerous factor causing arterial sclerosis diseases (e.g., coronary diseases, cerebrovascular diseases, aortic diseases and peripheral arterial diseases) and ischemic heart diseases (e.g., angina pectoris and cardiac infarction), giving rise to a serious problem. Hyper lipidemia is defined as one showing any one or two or more of the followings: cholesterol in blood is 220 mg/dl or more, neutral lipid is 150 mg/dl or more and hyperbaric lipoprotein (HDL)-cholesterol is less than 35 mg/dl (Guideline of Japan Society of Arterial Sclerosis) and is catastrophic diseases causing arterial sclerosis and the like. One of the major reasons is a rise in the level of LDL-cholesterol in blood (high cholesteremia) and the deposition of cholesterol on the inner wall of a blood vessel. At present, treatment performed to reduce serum cholesterol has come to be thought effective to prevent the development and progress of arterial sclerosis and the like. A cholesterol biosynthesis inhibitor, especially, an inhibitor of 3-hydroxy-3-methyl glutaryl-CoA (HMG-CoA) reducing enzyme such as pravastatin has obtained good results as a medicine for reducing serum cholesterol in recent years instead of conventional fibrate type drugs and nicotinic acid preparations. The HMG-CoA reducing enzyme inhibitor competitively inhibits the HMG-CoA reducing enzyme which is an enzyme limiting the rate of biosynthesis of cholesterol in the liver to decrease the rate of biosynthesis of cholesterol, whereby the liver is increased in the ability to synthesize LDL acceptors, with the result that the serum LDL is decreased. However, the inhibition of the production of mevalonic acid based on the inhibition of the HMG-CoA reducing enzyme affects the production of isoprene including farnecyl diphosphoric acid (FPP). Therefore, there is a fear as to an influence on, for example, other metabolic substances, such as ubiquinone, dolichol, heme A, isopentenyl tRNA and prenyl protein, produced through isoprene as a synthetic intermediate. Further, risks of side effects such as cataract and myopathy have been pointed out.
The squalene synthesizing enzyme is a membrane-bound enzyme of 47-kDa and reducibly catalyzes the head-to-head condensation of two molecules of FPP to synthesize squalene which is an intermediate for the synthesis of cholesterol. In a cholesterol-biosynthesizing system, the squalene synthesizing enzyme is positioned downstream of a system generating the HMG-CoA reducing enzyme and isoprene and therefore the squalene synthesizing enzyme inhibitor is considered to have almost no effect on metabolic systems other than cholesterol and is therefore expected to work as a new cholesterol depressor which will solve the problems concerning the HMG-CoA reducing enzyme inhibitor. A squalene synthesizing enzyme inhibitor which was reported first is analogous compounds of FPP and squalene. However, these analogous compounds has an activity inhibiting the formation of prenyl protein and the like in addition to squalene synthesizing enzyme inhibitive action and it is difficult to put these analogous compounds to practical use. In the meantime, it has been disclosed recently that a certain type substituted phenylethynylquinuclidine compound and substituted pyridinylethynylquinuclidine compound are useful as a squalene synthesizing enzyme inhibitor in JP-A 7-502283, 8-502731, 8-504803 (U.S. Pat. No. 5,731,323) and 8-509488. However, no squalene synthesizing enzyme inhibitor which can produce an effect as a medicine for hyper lipidemia has been created so far.
That is, an object of the present invention is to search and to find a compound which has stronger squalene synthesizing enzyme inhibitive activities and cholesterol depressing action over those currently in use and is useful as a remedy for hyper lipidemia.
In view of the above situation, the inventors of the present invention have made earnest studies and as a result, found that a specific quinuclidine compound and its salt have unprecedented strong squalene synthesizing inhibitive activities. The inventors have also found that these compounds and their salts have strong cholesterol biosynthesizing inhibitive activities, triglyceride biosynthesizing inhibitive activities and serum cholesterol depressing action and serum triglyceride depressing action based on the squalene synthesizing inhibitive activities. The present invention has been thus completed. A compound according to the present invention is useful as a remedy for hyper lipidemia.
Accordingly, the present invention relates to:
(1) a compound (I) represented by the following formula: 
(in which R1 represents (1) hydrogen atom or (2) hydroxyl group; HAr represents an aromatic heterocycle which may be substituted with 1 to 3 groups; Ar represents an optionally substituted aromatic ring; W represents a chain represented by (1) xe2x80x94CH2xe2x80x94CH2xe2x80x94 which may be substituted, (2) xe2x80x94CHxe2x95x90CHxe2x80x94 which may be substituted, (3) xe2x80x94Cxe2x89xa1Cxe2x80x94, (4) xe2x80x94NHxe2x80x94COxe2x80x94, (5) xe2x80x94COxe2x80x94NHxe2x80x94, (6) xe2x80x94NHxe2x80x94CH2xe2x80x94, (7) xe2x80x94CH2xe2x80x94NHxe2x80x94, (8) xe2x80x94CH2xe2x80x94COxe2x80x94, (9) xe2x80x94COxe2x80x94CH2xe2x80x94, (10) xe2x80x94NHxe2x80x94S(O)lxe2x80x94, (11) xe2x80x94S(O)lxe2x80x94NHxe2x80x94, (12) xe2x80x94CH2xe2x80x94S(O)lxe2x80x94 or (13) xe2x80x94S(O)lxe2x80x94CH2xe2x80x94 (l denotes 0, 1 or 2); and X represents a chain represented by (1) a single bond, (2) an optionally substituted C1-6 alkylene chain, (3) an optionally substituted C2-6 alkenylene chain, (4) an optionally substituted C2-6 alkynylene chain, (5) a formula xe2x80x94Qxe2x80x94 (wherein Q represents oxygen atom, sulfur atom, CO or N(R2) (wherein R2 represents a C1-6 alkyl group or a C1-6 alkoxy group)), (6) xe2x80x94NHxe2x80x94COxe2x80x94, (7) xe2x80x94COxe2x80x94NHxe2x80x94, (8) xe2x80x94NHxe2x80x94CH2xe2x80x94, (9) xe2x80x94CH2xe2x80x94NHxe2x80x94, (10) xe2x80x94CH2xe2x80x94COxe2x80x94, (11) xe2x80x94COxe2x80x94CH2xe2x80x94, (12) xe2x80x94NHxe2x80x94S(O)mxe2x80x94, (13) xe2x80x94S(O)mxe2x80x94NHxe2x80x94, (14) xe2x80x94CH2xe2x80x94S(O)mxe2x80x94, (15) xe2x80x94S(O)mxe2x80x94CH2xe2x80x94 (wherein m denotes 0, 1 or 2) or (16) xe2x80x94(CH2)nxe2x80x94Oxe2x80x94 (wherein n denotes an integer from 1 to 6)), a salt thereof or a hydrate of them,
(2) the compound described in (1), a salt thereof or a hydrate of them, wherein R1 represents (1) hydrogen atom or (2) hydroxyl group; HAr is a 5- to 14-membered aromatic heterocycle which contains 1 to 4 atoms selected from nitrogen atom, sulfur atom and oxygen atom and may be substituted with 1 to 3 groups selected from (1) a halogen atom, (2) hydroxyl group, (3) thiol group, (4) nitro group, (5) nitrile group, (6) a C1-6 chain hydrocarbon group which may be substituted, (7) a C3-8 cyclic hydrocarbon group which may be substituted, (8) a C6-14 aromatic cyclic hydrocarbon group which may be substituted, (9) a 5- to 14-membered aromatic heterocyclic group which may be substituted, (10) a 4- to 10-membered non-aromatic heterocyclic group which may be substituted, (11) a C1-6 alkoxy group which may be substituted, (12) a C3-8 cycloalkyloxy group which may be substituted, (13) a C1-6 chain hydrocarbon-thio group which may be substituted, (14) a C3-8 cyclic hydrocarbon-thio group which may be substituted, (15) a C6-14 aromatic hydrocarbonoxy group which may be substituted, (16) a 5- to 14-membered heterocycle-oxy group which may be substituted, (17) a C6-14 aromatic hydrocarbon-thio group which may be substituted, (18) a 5- to 14-membered heterocycle-thio group which may be substituted, (19) an amino group which may be substituted, (20) azide group, (21) guanidino group, (22) carbamide group, (23) formyl group, (24) a C1-6 imidoyl group which may be substituted, (25) a substituted carbonyl group, (26) a substituted carbonyl-oxy group, (27) a carboxyl group which may form a salt, (28) a carbamoyl group which may be substituted, (29) a C1-4 alkylenedioxy group which may be substituted, (30) a sulfinyl group which may be substituted and (31) a sulfonyl group which may be substituted; Ar is a C6-14 aromatic hydrocarbon ring or a 5- to 14-membered aromatic heterocycle which may be substituted with one or more groups selected from (1) hydroxyl group, (2) a halogen atom, (3) a C1-6 chain hydrocarbon group which may be substituted, (4) a C3-8 cyclic hydrocarbon group which may be substituted, (5) a C1-6 alkoxy group which may be substituted, (6) a C3-8 cycloalkyloxy group which may be substituted, (7) a C1-6 chain hydrocarbon-thio group which may be substituted, (8) a C3-8 cyclic hydrocarbon-thio group, (9) a C6-14 aromatic hydrocarbon cyclic group which may be substituted, (10) a 5- to 14-membered heterocyclic group which may be substituted, (11) an amino group which may be substituted with a C1-6 alkyl group and (12) a C1-4 alkylenedioxy group; W is a chain represented by (1) xe2x80x94CH2xe2x80x94CH2xe2x80x94 which may be substituted, (2) xe2x80x94CHxe2x95x90CHxe2x80x94 which may be substituted, (3) xe2x80x94Cxe2x89xa1Cxe2x80x94, (4) xe2x80x94NHxe2x80x94COxe2x80x94, (5) xe2x80x94COxe2x80x94NHxe2x80x94, (6) xe2x80x94NHxe2x80x94CH2xe2x80x94, (7) xe2x80x94CH2xe2x80x94NHxe2x80x94, (8) xe2x80x94CH2xe2x80x94COxe2x80x94, (9) xe2x80x94COxe2x80x94CH2xe2x80x94, (10) xe2x80x94NHxe2x80x94S(O)lxe2x80x94, (11) xe2x80x94S(O)lxe2x80x94NHxe2x80x94, (12) xe2x80x94CH2xe2x80x94S(O)lxe2x80x94 or (13) xe2x80x94S(O)lxe2x80x94CH2xe2x80x94 (l denotes 0, 1 or 2); and X represents a chain represented by (1) a single bond, (2) a C1-6 alkylene chain which may be substituted, (3) a C2-6 alkenylene chain which may be substituted, (4) a C2-6 alkynylene chain which may be substituted, (5) the formula xe2x80x94Qxe2x80x94 (wherein Q represents oxygen atom, sulfur atom, CO or N(R2) (wherein R2 represents a C1-6 alkyl group or a C1-6 alkoxy group)), (6) xe2x80x94NHxe2x80x94COxe2x80x94, (7) xe2x80x94COxe2x80x94NHxe2x80x94, (8) xe2x80x94NHxe2x80x94CH2xe2x80x94, (9) xe2x80x94CH2xe2x80x94NHxe2x80x94, (10) xe2x80x94CH2xe2x80x94COxe2x80x94, (11) xe2x80x94COxe2x80x94CH2xe2x80x94, (12) xe2x80x94NHxe2x80x94S(O)mxe2x80x94, (13) xe2x80x94S(O)mxe2x80x94NHxe2x80x94, (14) xe2x80x94CH2xe2x80x94S(O)mxe2x80x94, (15) xe2x80x94S(O)mxe2x80x94CH2xe2x80x94 (wherein m denotes 0, 1 or 2) or (16) xe2x80x94(CH2)nxe2x80x94Oxe2x80x94 (wherein n represents an integer from 1 to 6),
(3) the compound described in (1) or (2), a salt thereof or a hydrate of them, in which R1 is hydroxyl group,
(4) the compound described in (1) or (2), a salt thereof or a hydrate of them, in which W is xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94,
(5) the compound described in 1) or 2), a salt thereof or a hydrate of them, in which X is a single bond, xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94COxe2x80x94,
(6) the compound described in (1) or (2), a salt thereof or a hydrate of them, wherein HAr is a 5- to 14-membered aromatic heterocycle containing 1 to 4 atoms selected from nitrogen atom, sulfur atom and oxygen atom and may be substituted with 1 to 3 groups selected from (1) hydroxyl group, (2) a halogen atom, (3) thiol group, (4) nitro group, (5) nitrile group, (6) a C1-6 alkyl group, C2-6 alkenyl group or C2-6 alkynyl group, which may be substituted with one or two groups selected from (a) a hydroxyl group which may be protected, (b) a halogen atom, (c) nitrile group, (d) carboxyl group, (e) a C3-8 cycloalkyl group, C3-8 cycloalkenyl group or C3-8 cycloalkynyl group, which may be hydroxylated or halogenated, (f) a C1-6 alkoxy group which may be substituted with a group selected from a halogen atom, hydroxyl group, a C6-14 aryl group, a 5- to 14-membered heteroaryl group and a C6-14 aryl-C1-6 alkoxy group, (g) a C3-8 cycloalkyloxy group which may be halogenated or hydroxylated, (h) a C3-8 cycloalkenyloxy group which may be halogenated or hydroxylated, (i) a 5- to 14 -membered aryl-oxy group which may be halogenated or hydroxylated, (j) a 5- to 14 membered non-aromatic cycle-oxy group which may be halogenated or hydroxylated, (k) a C1-6 alkoxy-carbonyl group, (l) a C1-4 alkylenedioxy group which may be halogenated, (m) a C1-6 alkanoyl group which may be substituted with a group selected from hydroxyl group, a C1-6 alkoxy group and a C1-6 alkanoyloxy group, (n) a C6-14 aryl group which may be substituted with a group selected from a halogen atom, a C1-6 alkyl group and a C1-6 alkoxy group, (o) a 5- to 14-membered aromatic heterocyclic group which may be substituted with a group selected from a halogen atom, a C1-6 alkyl group, a C3-8 alkenyl group, a C3-8 alkynyl group and a C1-6 alkoxy group, (p) a 5- to 10-membered non-aromatic heterocyclic group which may be substituted with a group selected from a halogen atom, a C1-6 alkyl group, a C3-8 alkenyl group, a C3-8 alkynyl group and a C1-6 alkoxy group, (q) a group (EtO)2POxe2x80x94, (r) acetyl group, (s) a sulfonyl group which may be substituted with a group selected from a C1-6 hydrocarbon group, a mono-(C1-6 hydrocarbon)-amino group and a di-(C1-6 hydrocarbon)-amino group, (t) an amino group which may be substituted with a C1-6 hydrocarbon group, (u) a C1-6 hydrocarbon group-thio group which may be hydroxylated or halogenated and (v) a carbamoyl group which may be substituted with a C1-6 hydrocarbon group, (7) a C3-8 cycloalkyl group or C3-8 cycloalkenyl group which may be substituted with one or two groups selected from (a) hydroxyl group, (b) a halogen atom, (c) nitrile group, (d) carboxyl group, (e) a C1-6 alkyl group which may be substituted with a group selected from a C1-6 alkoxy group which may be hydroxylated or halogenated, a C1-6 hydrocarbon-thio group which may be halogenated, an amino group which may be substituted with a C1-6 hydrocarbon group and a C1-6 alkanoyl group, (f) a C1-6 alkenyl group which may be substituted with a group selected from a C1-6 alkoxy group which may be hydroxylated or halogenated, a C1-6 hydrocarbon-thio group which maybe halogenated, an amino group which may be substituted with a C1-6 hydrocarbon group and a C1-6 alkanoyl group, (g) a C1-6 alkynyl group which may be substituted with a group selected from a C1-6 alkoxy group which may be hydroxylated or halogenated, a C1-6 hydrocarbon-thio group which may be halogenated, an amino group which may be substituted with a C1-6 hydrocarbon group and a C1-6 alkanoyl group, (h) an amino group which may be substituted with a group selected from a C1-6 alkoxy group which may be hydroxylated or halogenated, a C1-6 hydrocarbon-thio group which may be halogenated, a C1-6 alkanoyl group and a C1-6 hydrocarbon group, (i) a C1-6 alkoxy group which may be substituted with a group selected from a C1-6 alkyl group which may be hydroxylated or halogenated, a C1-6 alkoxy group which may be hydroxylated or halogenated, a C1-6 hydrocarbon-thio group which may be halogenated, an amino group which may be substituted with a C1-6 hydrocarbon group and a C1-6 alkanoyl group, (j) a C1-6 hydrocarbon-thio group which may be substituted with a group selected from a C1-6 alkyl group which may be hydroxylated or halogenated, a C1-6 alkenyl group which may be halogenated, a C1-6 alkynyl group which may be halogenated, a C1-6 alkoxy group which may be hydroxylated or halogenated, a C1-6 hydrocarbon-thio group which may be halogenated, an amino group which may be substituted with a C1-6 hydrocarbon group and a C1-6 alkanoyl group, (k) a C1-6 alkanoyl group which may be substituted with a group selected from hydroxyl group, a C1-6 alkoxy group and a C1-6 alkanoyloxy group, (l) a C6-14 aryl group which may be substituted with a group selected from a halogen atom, a C1-6 alkyl group and a C1-6 alkoxy group, (m) a 5- to 14-membered aromatic heterocyclic group which may be substituted with a group selected from a halogen atom, a C1-6 alkyl group, a C3-8 alkenyl group, a C3-8 alkynyl group and a C1-6 alkoxy group, (n) a non-aromatic heterocyclic group which may be substituted with a group selected from a halogen atom, a C1-6 alkyl group, a C3-8 alkenyl group, a C3-8 alkynyl group and a C1-6 alkoxy group, (o) a C1-6 alkoxy-carbonyl group, (p) a C1-4 alkylenedioxy group which may be halogenated, (q) a group (EtO)2POxe2x80x94 and (r) acetyl group, (8) a C6-14 aromatic hydrocarbon group which may be substituted with one or more groups selected from (a) hydroxyl group, (b) a halogen atom, (c) a C1-6 alkyl-sulfonyl group, C1-6 alkenyl-sulfonyl group and C1-6 alkynyl-sulfonyl group, which may be halogenated, (d) a C1-4 alkylenedioxy group which may be halogenated, (e) a C1-6 alkoxy group which may be halogenated, (f) a C1-6 hydrocarbon-thio group which may be halogenated, (g) a C1-6 alkoxy-carbonyl group, (h) a C6-14 aryl-C1-6 alkoxy group, (i) a C1-7 alkanoylamino group, (j) a C1-6 alkyl-carbamoyl group, (k) a C1-6 alkenyl-carbamoyl group, (l) a C1-6 alkynyl-carbamoyl group and (m) an amino group which may be substituted with a C1-6 hydrocarbon group, (9) a 5- to 14-membered aromatic heterocyclic group which may be substituted with one or more groups selected from (a) hydroxyl group, (b) a halogen atom, (c) nitrile group, (d) a C1-6 alkyl group, C1-6 alkenyl group or C1-6 alkynyl group, which may be halogenated, (e) a C1-6 alkoxy group which may be halogenated, (f) a C1-6 alkylthio group, C1-6 alkenylthio group or C1-6 alkynylthio group which may be halogenated, (g) a C1-6 alkoxy-C1-6 alkyl group, (h) acetyl group, (i) an C1-6 alkanoyl group, (j) a mono-(C1-6 hydrocarbon)-amino group, (k) a di-(C1-6 hydrocarbon)-amino group and (l) a tri-(C1-6 hydrocarbon)-amino group, (10) a 4- to 10-membered non-aromatic heterocyclic group which may be substituted with one or more groups selected from (a) hydroxyl group, (b) a halogen atom, (c) nitrile group, (d) a C1-6 alkyl group, C1-6 alkenyl group or C1-6 alkynyl group, which may be halogenated, (e) a C1-6 alkoxy group which may be halogenated, (f) a C1-6 alkylthio group, C1-6 alkenylthio group or C1-6 alkynylthio group, which may be halogenated, (g) a C1-6 alkoxy-C1-6 alkyl group, (h) acetyl group, (i) a C1-6 alkanoyl group, (j) a mono-(C1-6 hydrocarbon)-amino group, (k) a di-(C1-6 hydrocarbon)-amino group and (l) a tri-(C1-6 hydrocarbon)-amino group, (m) a C1-4 alkylenedioxy group and (n) an oxo group, (11) a C1-6 alkoxy group which may be substituted with one or more groups selected from (a) hydroxyl group, (b) a halogen atom, (c) a C1-6 alkyl group, C1-6 alkenyl group or C1-6 alkynyl group, which may be substituted with a group selected from hydroxyl group, a halogen atom, a 5- to 14-membered aromatic heterocyclic group and a 4 to 10-membered non-aromatic heterocyclic group, (d) a C3-8 cycloalkyl group or C3-8 cycloalkenyl group which may be hydroxylated or halogenated, (e) a C1-6 alkoxy group which may be hydroxylated or halogenated, (f) a C1-6 alkylthio group, C1-6 alkenylthio group or C1-6 alkynylthio group, which may be halogenated, (g) a C3-8 cycloalkyloxy group or C3-8 cycloalkenyloxy group which may be halogenated, (h) a C3-8 cycloalkylthio group or C3-8 cycloalkenylthio group which may be halogenated, (i) a C6-14 aryl group, (j) a C1-6 alkanoyl group which may be halogenated, (k) a 5- to 14-membered aromatic heterocyclic group and (l) a 4- to 10-membered non-aromatic heterocyclic group, (12) a C3-8 cycloalkyloxy group which may be substituted with one or two groups selected from (a) hydroxyl group, (b) a halogen atom, (c) a C1-6 a hydrocarbon group which may be substituted with a group selected from hydroxyl group, a halogen atom, a C1-6 alkoxy group and a C1-6 alkanoyl group, (d) a C1-6 alkoxy group which may be substituted with a group selected from a halogen atom, a C1-6 alkoxy group and a C1-6 alkanoyl group and (e) a C1-6 hydrocarbon-thio group which may be substituted with a group selected from a halogen atom, a C1-6 alkoxy group and a C1-6 alkanoyl group, (13) a C1-6 alkylthio group, C1-6 alkenylthio group or C1-6 alkynylthio group, which may be substituted with one or two groups selected from (a) hydroxyl group, (b) a halogen atom, (c) a C1-6 alkyl group, C1-6 alkenyl group or C1-6 alkynyl group which may be substituted with a group selected from hydroxyl group, a halogen atom, a 5- to 14-membered aromatic heterocyclic group and 4- to 10-membered non-aromatic heterocyclic group, (d) a C3-8 cycloalkyl group, C3-8 cycloalkenyl group or C3-8 cycloalkynyl group, which may be hydroxylated or halogenated, (e) a C1-6 alkoxy group which may be hydroxylated or halogenated, (f) a C1-6 alkylthio group, C1-6 alkenylthio group or C1-6 alkynylthio group, which may be halogenated, (g) a C3-8 cycloalkyloxy group or C3-8 cycloalkenyloxy group which may be halogenated, (h) a C3-8 cycloalkylthio group or C3-8 cycloalkenylthio group which may be halogenated, (i) a C6-14 aryl group, (j) a C1-6 alkanoyl group which may be halogenated, (k) a 5- to 14-membered aromatic heterocyclic group and (l) a 4- to 10-membered non-aromatic heterocycle, (14) a C3-8 cycloalkylthio group or a C3-8 cycloalkenylthio group which may be substituted with one or two groups selected from (a) hydroxyl group, (b) a halogen atom, (c) a C3-8 alkyl group, C3-8 alkenyl group or C3-8 alkynyl group, which may be halogenated, (d) a C1-6 alkoxy group which may be halogenated, (e) a C1-6 hydrocarbon-thio group which may be halogenated and (f) a C1-6 alkanoyl group which may be halogenated, (15) an amino group represented by the formula xe2x80x94N(R3)R4 (wherein R3 and R4 are the same as or different from each other and each represents a group selected from (a) an aromatic heterocyclic group, (b) a non-aromatic heterocyclic group, (c) a C1-6 alkyl group, C1-6 alkenyl group or C1-6 alkynyl group, which may be substituted with a halogen atom or a C1-6 alkoxy group, (d) a C3-8 cycloalkyl group or a C3-8 cycloalkenyl group which may be halogenated, (e) a carbonyl group which is substituted with a C1-6 alkyl group, C1-6 alkenyl group or C1-6 alkynyl group, which may be halogenated, a C3-8 cycloalkyl group or C3-8 cycloalkenyl group, which may be halogenated, a C1-6 alkoxy group which may be halogenated, a C6-14 aryl group or an aromatic heterocyclic group, (f) a C1-6 alkanoyl group which may be substituted with a group selected from a C6-14 aryl group and an aromatic heterocyclic group, (g) a carbamoyl group which may be substituted with a C1-6 alkyl group, a C1-6 alkenyl group, a C1-6 alkynyl group, a C6-14 aryl group or an aromatic heterocyclic group and (h) a sulfonyl group which is substituted with a C1-6 alkyl group, a C1-6 alkenyl group or a C1-6 alkynyl group, and also, (i) R3 and R4 may be combined and united to form a 3- to 10-membered ring and the cyclic amino group may be substituted with one or more groups selected from hydroxyl group, a halogen atom, a C1-6 alkyl group, a C1-6 alkenyl group, a C1-6 alkynyl group, a C1-6 alkoxy group, a C1-6 hydrocarbon-thio group and a C1-4 alkylenedioxy group), (16) a C6-14 aryl-oxy group which may be substituted with one or more groups selected from (a) hydroxyl group, (b) a halogen atom, (c) a C1-6 alkyl-sulfonyl group, C1-6 alkenyl-sulfonyl group or C1-6 alkynyl-sulfonyl group which may be halogenated, (d) a C1-4 alkylenedioxy group which may be halogenated, (e) a C1-6 alkoxy group which may be halogenated, (f) a C1-6 hydrocarbon-thio group which may be halogenated, (g) a C1-6 alkoxy-carbonyl group, (h) a C6-14 aryl-C1-6 alkoxy group, (i) a C1-7 alkanoylamino group, (j) a C1-6 alkyl-carbamoyl group, (k) a C1-6 alkenyl-carbamoyl group, (l) a C1-6 alkynyl-carbamoyl group and (m) an amino group which may be substituted with a C1-6 hydrocarbon group, (17) a C6-14 aryl-thio group which may be substituted with one or more groups selected from (a) hydroxyl group, (b) a halogen atom, (c) a C1-6 alkyl-sulfonyl group, C1-6 alkenyl-sulfonyl group or C1-6 alkynyl-sulfonyl group, which may be halogenated, (d) a C1-4 alkylenedioxy group which may be halogenated, (e) a C1-6 alkoxy group which may be halogenated, (f) a C1-6 hydrocarbon-thio group which may be halogenated, (g) a C1-6 alkoxy-carbonyl group, (h) a C6-14 aryl-C1-6 alkoxy group, (i) a C1-7 alkanoylamino group (j) a C1-6 alkyl-carbamoyl group, (k) a C1-6 alkenyl-carbamoyl group, (l) a C1-6 alkynyl-carbamoyl group and (m) an amino group which may be substituted with a C1-6 hydrocarbon group, (18) a 5- to 15-membered aromatic heterocycle-oxy group which may be substituted one or more groups selected from (a) hydroxyl group, (b) a halogen atom, (c) nitrile group, (d) a C1-6 alkyl group, C1-6 alkenyl group or C1-6 alkynyl group, which may be halogenated, (e) a C1-6 alkoxy group which may be halogenated, (f) a C1-6 alkylthio group, C1-6 alkenylthio group or C1-6 alkynylthio group, which may be halogenated, (g) a C1-6 alkoxy-C1-6 alkyl group, (h) acetyl group, (i) a C1-6 alkanoyl group, (j) a mono-(C1-6 hydrocarbon)-amino group, (k) a di-(C1-6 hydrocarbon)-amino group and (l) a tri-(C1-6 hydrocarbon)-amino group, (19) a 5- to 15-membered aromatic heterocycle-thio group which may be substituted one or more groups selected from (a) hydroxyl group, (b) a halogen atom, (c) nitrile group, (d) a C1-6 alkyl group, C1-6 alkenyl group or C1-6 alkynyl group, which may be halogenated, (e) a C1-6 alkoxy group which may be halogenated, (f) a C1-6 alkylthio group, C1-6 alkenylthio group or C1-6 alkynylthio group, which may be halogenated, (g) a C1-6 alkoxy-C1-6 alkyl group, (h) acetyl group, (i) a C1-6 alkanoyl group, (j) a mono-(C1-6 hydrocarbon)-amino group, (k) a di-(C1-6 hydrocarbon)-amino group and (l) a tri-(C1-6 hydrocarbon)-amino group, (20) a 4- to 10-membered non-aromatic heterocycle-oxy group which may be substituted one or more groups selected from (a) hydroxyl group, (b) a halogen atom, (c) nitrile group, (d) a C1-6 alkyl group, C1-6 alkenyl group or C1-6 alkynyl group, which may be halogenated, (e) a C1-6 alkoxy group which may be halogenated, (f) a C1-6 alkylthio group, C1-6 alkenylthio group or C1-6 alkynylthio group which may be halogenated, (g) a C1-6 alkoxy-C1-6 alkyl group, (h) acetyl group, (i) a C1-6 alkanoyl group, (j) a mono-(C1-6 hydrocarbon)-amino group, (k) a di-(C1-6 hydrocarbon)-amino group and (l) a tri-(C1-6 hydrocarbon)-amino group, (21) a 4- to 10-membered non-aromatic heterocycle-thio group which may be substituted one or more groups selected from (a) hydroxyl group, (b) a halogen atom, (c) nitrile group, (d) a C1-6 alkyl group, C1-6 alkenyl group or C1-6 alkynyl group, which may be halogenated, (e) a C1-6 alkoxy group which may be halogenated, (f) a C1-6 alkylthio group, C1-6 alkenylthio group or C1-6 alkynylthio group which may be halogenated, (g) a C1-6 alkoxy-C1-6 alkyl group, (h) acetyl group, (i) a C1-6 alkanoyl group, (j) a mono-(C1-6 hydrocarbon)-amino group, (k) a di-(C1-6 hydrocarbon)-amino group and (l) a tri-(C1-6 hydrocarbon)-amino group, (22) azide group, (23) guanidino group, (24) carbamide group, (25) formyl group, (26) a C1-6 imidoyl group which may be substituted, (27) a C1-6 alkanoyl group which may be substituted with a C1-6 alkoxy group, (28) a C1-6 alkanoyl-oxy group which may be substituted with a C1-6 alkoxy group, (29) a carboxyl group which may form a salt, (30) a carbonyl group which is substituted with a group selected from (a) a C1-6 alkoxy group, (b) a C6-14 aryl group and (c) a 5- to 14-membered aromatic heterocyclic group, (31) a carbamoyl group represented by the formula xe2x80x94COxe2x80x94N(R5)R6 (wherein R5 and R6 are the same as or different from each other and each represents a group selected from (a) hydrogen atom, (b) a C1-6 alkyl group, (c) a C1-6 alkenyl group, (d) a C1-6 alkynyl group, (e) a C3-8 cycloalkyl group, (f) a C3-8 cycloalkenyl group, (g) a C6-14 aryl group and (h) an aromatic heterocyclic group or (i) R5 and R6 may be combined and united to form a 3- to 8-membered ring), (32) a C1-4 alkylenedioxy group which may be substituted with (a) hydroxyl group or (b) a halogen atom, (33) a sulfinyl group which may be substituted with a group selected from (a) a C1-6 hydrocarbon group which may be halogenated and (b) an amino group which may be mono-substituted or di-substituted with a C1-6 hydrocarbon group which may be halogenated and (34) a sulfonyl group which may be substituted with (a) a C1-6 hydrocarbon group which may be halogenated or (b) an amino group which may be mono-substituted or di-substituted with a C1-6 hydrocarbon group which may be halogenated,
(7) the compound described in (1) or (2), a salt thereof or a hydrate of them, wherein HAr is a 5- to 14-membered aromatic heterocycle which may be substituted with, in addition to a substituent xe2x80x94Xxe2x80x94Ar, 1 to 3 groups selected from (1) a 5- or 6-membered aromatic heterocycle which may be substituted with a C1-6 alkyl group, (2) a 5- to 6-membered non-aromatic heterocycle which may be substituted with one or more groups selected from (a) hydroxyl group, (b) a C1-6 alkyl group and (c) a C1-6 alkoxy group, (3) a C6-10 aromatic hydrocarbon ring which may be substituted with one or more groups selected from (a) a halogen atom, (b) a C1-6 alkoxy group, (c) a C1-4 alkylenedioxy group and (d) a sulfonyl group which may be substituted with a C1-6 alkyl group, (4) a C1-6 alkyl group which may be substituted with one or more groups selected from (a) hydroxyl group, (b) a halogen atom, (c) a 5- or 6-membered aromatic heterocycle and (d) a C1-6 alkoxy group and (5) a C1-6 alkoxy group which may be substituted with (a) a halogen atom or (b) a C1-6 alkoxy group,
(8) the compound described in (1) or (2), a salt thereof or a hydrate of them, wherein HAr is a 5- to 10-membered aromatic heterocycle which may be substituted with, in addition to a substituent xe2x80x94Xxe2x80x94Ar, 1 to 3 groups selected from (1) a benzene ring which may be substituted with a C1-4 alkylenedioxy group, (2) pyridine ring, (3) pyrimidine ring, (4) pyridazine ring, (5) pyrazine ring, (6) thiophene ring, (7) a piperidine ring which may be substituted with a C1-6 alkoxy group, (8) a piperazine ring which may be substituted with a C1-6 alkoxy group, (9) a pyrrolidine ring which may be substituted with a C1-6 alkoxy group, (10) a piperidine ring which is substituted with hydroxyl group and a C1-6 alkoxy group, (11) a piperazine ring which is substituted with hydroxyl group and a C1-6 alkoxy group, (12) a pyrrolidine ring which is substituted with hydroxyl group and a C1-6 alkoxy group, (13) morpholine ring, (14) a C1-6 alkyl group which may be substituted with a C1-6 alkoxy group and (15) a C1-6 alkoxy group which may be substituted with hydroxyl group or a C1-6 alkoxy group,
(9) the compound described in (1) or (2), a salt thereof or a hydrate of them, in which HAr is a pyridine ring, pyrimidine ring, pyridazine ring, pyrazine ring, indole ring, quinoline ring, thiophene ring or benzothiophene ring which may be substituted with 1 to 3 groups,
(10) the compound described in (1) or (2), a salt thereof or a hydrate of them, wherein HAr is a pyridine ring, pyrimidine ring, pyridazine ring, pyrazine ring, indole ring, quinoline ring, thiophene ring or benzothiophene ring, which may be substituted with, in addition to a substituent xe2x80x94Xxe2x80x94Ar, 1 to 3 groups selected from (1) a 5- or 6-membered aromatic heterocycle which may be substituted with a C1-6 alkyl group, (2) a 5- or 6-membered aromatic heterocycle which may be substituted with one or more groups selected from (a) hydroxyl group, (b) a C1-6 alkyl group and (c) a C1-6 alkoxy group, (3) a C6-10 aromatic hydrocarbon ring which may be substituted with one or more groups selected from (a) a halogen atom, (b) a C1-6 alkoxy group, (c) a C1-4 alkylenedioxy group and (d) a sulfonyl group which may be substituted with a C1-6 alkyl group, (4) a C1-6 alkyl group which may be substituted with one or more groups selected from (a) hydroxyl group, (b) a halogen atom, (c) a 5- or 6-membered heterocycle and (d) a C1-6 alkoxy group and (5) a C1-6 alkoxy group which may be substituted with (a) a halogen atom and (b) a C1-6 alkoxy group,
(11) the compound described in (1) or (2), a salt thereof or a hydrate of them, wherein Ar is a C6-14 aromatic hydrocarbon ring or 5- to 14-membered aromatic heterocycle, which may have 1 to 3 substituents selected from (1) a halogen atom, (2) a C1-6 alkyl group, C2-6 alkenyl group or C2-6 alkynyl group, which may be substituted with one or more groups selected from (a) a halogen atom, (b) a C1-6 alkoxy group and (c) a sulfonyl group which may be substituted, (3) a C1-6 alkoxy group which may be halogenated, (4) a mono-(C1-6 alkyl)-amino group, (5) a di-(C1-6 alkyl)-amino group and (6) a C1-4 alkylenedioxy group which may be halogenated,
(12) the compound described in (1) or (2), a salt thereof or a hydrate of them, in which Ar is an optionally substituted benzene ring or pyridine ring,
(14) the compound described in (1) or (2), a salt thereof or a hydrate of them, in which X is xe2x80x94CH2xe2x80x94; and Ar is benzene ring,
(15) the compound described in (1) or (2) in which the compound is represented by the following formula: 
(in the formula, HAr represents a 5- to 10-membered aromatic heterocycle containing 1 to 4 atoms selected from nitrogen atom, sulfur atom and oxygen atom and may be substituted with 1 to 3 groups selected from (1) a halogen atom, (2) hydroxyl group, (3) thiol group, (4) nitro group, (5) nitrile group, (6) a C1-6 chain hydrocarbon group which may be substituted, (7) a C3-8 cyclic hydrocarbon group which may be substituted, (8) a C6-14 aromatic cyclic hydrocarbon group which may be substituted, (9) a 5- to 14-membered aromatic heterocyclic group which may be substituted, (10) a 4- to 10-membered non-aromatic heterocyclic group which may be substituted, (11) a C1-6 alkoxy group which may be substituted, (12) a C3-8 cycloalkyloxy group which may be substituted, (13) a C1-6 chain hydrocarbon-thio group which may be substituted, (14) a C3-8 cyclic hydrocarbon-thio group which may be substituted, (15) a C6-14 aromatic hydrocarbon-oxy group which may be substituted, (16) a 5- to 14-membered heterocycle-oxy group which may be substituted, (17) a C6-14 aromatic hydrocarbon-thio group which may be substituted, (18) a 5- to 14-membered heterocycle-thio group which may be substituted, (19) an amino group which may be substituted, (20) azide group, (21) guanidino group, (22) carbamide group, (23) a formyl group, (24) a C1-6 imidoyl group which may be substituted, (25) a substituted carbonyl group, (26) a substituted carbonyl-oxy group, (27) a carboxyl group which may form a salt, (28) a carbamoyl group which may be substituted, (29) a C1-4 alkylenedioxy group which may be substituted, (30) a sulfinyl group which may be substituted and (31) a sulfonyl group which may be substituted; Ar is a C6-14 aromatic hydrocarbon ring or 5- to 14-membered aromatic heterocycle, which may be substituted with a group selected from (1) hydroxyl group, (2) a halogen atom, (3) a C1-6 chain hydrocarbon group which may be substituted, (4) a C3-8 cyclic hydrocarbon group which may be substituted, (5) a C1-6 alkoxy group which may be substituted, (6) a C3-8 cycloalkyloxy group which may be substituted, (7) a C1-6 chain hydrocarbon-thio group which may be substituted, (8) a C3-8 cyclic hydrocarbon-thio group, (9) a C6-14 aromatic hydrocarbon cyclic group which may be substituted, (10) a 5- to 14-membered heterocyclic group which may be substituted, (11) an amino group which may be substituted with a C1-6 alkyl group and (12) a C1-4 alkylenedioxy group; and X represents a chain represented by (1) a single bond, (2) a C1-6 alkylene chain which may be substituted, (3) a C2-6 alkenylene chain which may be substituted, (4) a C2-6 alkynylene chain which may be substituted, (5) the formula xe2x80x94Qxe2x80x94 (wherein Q represents oxygen atom, sulfur atom, CO or N(R2) (wherein R2 represents a C1-6 alkyl group or a C1-6 alkoxy group)), (6) xe2x80x94NHxe2x80x94COxe2x80x94, (7) xe2x80x94COxe2x80x94NHxe2x80x94, (8) xe2x80x94NHxe2x80x94CH2xe2x80x94, (9) xe2x80x94CH2xe2x80x94NHxe2x80x94, (10) xe2x80x94CH2xe2x80x94COxe2x80x94, (11) xe2x80x94COxe2x80x94CH2xe2x80x94, (12) xe2x80x94NHxe2x80x94S(O)mxe2x80x94, (13) xe2x80x94S(O)mxe2x80x94NHxe2x80x94, (14) xe2x80x94CH2xe2x80x94S(O)mxe2x80x94, (15) xe2x80x94S(O)mxe2x80x94CH2xe2x80x94 (wherein m is 0, 1 or 2) or (16) xe2x80x94(CH2)nxe2x80x94Oxe2x80x94 (wherein n denotes an integer from 1 to 6)), a salt thereof or a hydrate of them,
(16) the compound described in (15), a salt thereof or a hydrate of them, in which HAr is a pyridine ring, pyrazine ring, pyrimidine ring or pyridazine ring, which may be substituted with, in addition to a substituent xe2x80x94Xxe2x80x94Ar, one or more groups selected from (1) a 5- or 6-membered aromatic heterocycle, (2) a 5- or 6-membered non-aromatic heterocycle which may be substituted with a C1-6 alkoxy group and (3) a C6-10 aromatic hydrocarbon ring; Ar is a benzene ring or pyridine ring which may be halogenated; and X is xe2x80x94CH2xe2x80x94,
(17) the compound described in (15), a salt thereof or a hydrate of them, in which HAr is a pyridine ring, pyrazine ring, pyrimidine ring or pyridazine ring, which may be substituted with, in addition to a substituent xe2x80x94Xxe2x80x94Ar, a group selected from (1) a C1-6 alkoxy group which may be substituted with hydroxyl group, (2) a C1-6 alkoxy-C1-6 alkoxy group and (3) a C1-6 alkoxy-C1-6 alkyl-amino group; Ar is an optionally halogenated benzene or pyridine ring; and X is xe2x80x94CH2xe2x80x94,
(18) the compound described in (15), a salt thereof or a hydrate of them, wherein HAr is a pyridine ring, pyrazine ring, pyrimidine ring or pyridazine ring, which may be substituted with, in addition to a substituent xe2x80x94Xxe2x80x94Ar, 1 to 3 groups selected from (1) a benzene ring which may be substituted with a C1-4 alkylenedioxy group, (2) pyridine ring, (3) pyrimidine ring, (4) pyridazine ring, (5) pyrazine ring, (6) thiophene ring, (7) a piperidine ring which may be substituted with a C1-6 alkoxy group, (8) a piperazine ring which may be substituted with a C1-6 alkoxy group, (9) a pyrrolidine ring which may be substituted with a C1-6 alkoxy group, (10) a piperidine ring which is substituted with hydroxyl group and a C1-6 alkoxy group, (11) a piperazine ring which is substituted with hydroxyl group and a C1-6 alkoxy group, (12) a pyrrolidine ring which is substituted with hydroxyl group and a C1-6 alkoxy group, (13) morpholine ring, (14) a C1-6 alkyl group which may be substituted with a C1-6 alkoxy group and (15) a C1-6 alkoxy group which may be substituted with hydroxyl group or a C1-6 alkoxy group; Ar is a benzene ring or pyridine ring, which may be halogenated; and X is xe2x80x94CH2xe2x80x94,
(19) the compound described in (1), a salt thereof or a hydrate of them, in which the compound is any one selected from 3-(4-benzyl-2-phenyl-5-pyrimidyl)ethynyl-3-quinuclidinol; 3-[4-benzyl-2-(2-pyridyl)-5-pyrimidyl]ethynyl-3-quinuclidinol; 3-[3-benzyl-5-(2-pyridyl)-2-pyridyl]ethynyl-3-quinuclidinol; 3-(3-benzyl-5-phenyl-2-pyridyl)ethynyl-3-quinuclidinol; 3-[3-benzyl-5-(3-pyridyl)-2-pyridyl]ethynyl-3-quinuclidinol; 3-[3-benzyl-5-(4-pyridyl)-2-pyridyl]ethynyl-3-quinuclidinol; 3-(3-benzyl-5-pyrazyl-2-pyridyl)ethynyl-3-quinuclidinol; 3-[3-benzyl-5-(2-ethoxycarbonylethyl)-2-pyridyl]ethynyl-3-quinuclidinol; 3-[3-benzyl-5-(3-oxobutyl)-2-pyridyl]ethynyl-3-quinuclidinol; 3-[3-benzyl-5-(3-hydroxybutyl)-2-pyridyl]ethynyl-3-quinuclidinol; 3-[2-benzyl-6-(3-methoxypropylamino)-3-pyridyl]ethynyl-3-quinuclidinol; 3-[2-benzyl-6-(2-methoxyethyloxy)-3-pyridyl]ethynyl-3-quinuclidinol; 3-[2-benzyl-6-(3-methoxypropyloxy)-3-pyridyl]ethynyl-3-quinuclidinol; 3-[2-benzyl-6-(4-pyridyl)-3-pyridyl]ethynyl-3-quinuclidinol; 3-[2-benzyl-6-(3-pyridyl)-3-pyridyl]ethynyl-3-quinuclidinol; 3-(2-benzyl-6-pyrazyl-3-pyridyl)ethynyl-3-quinuclidinol; 3-[2-benzyl-6-(2-pyridyl)-3-pyridyl]ethynyl-3-quinuclidinol; 3-[4-benzyl-2-(3-pyridyl)-5-pyrimidyl]ethynyl-3-quinuclidinol; 3-[4-benzyl-2-(3,4-methylenedioxyphenyl)-5-pyrimidyl]ethynyl-3-quinuclidinol; 3-[4-benzyl-2-(3,4-methylenedioxyphenyl)-5-pyridyl]ethynyl-3-quinuclidinol; 3-[4-benzyl-2-(2-pyridyl)-5-pyridyl]ethynyl-3-quinuclidinol; 3-[4-benzyl-2-(3-pyridyl)-5-pyridyl]ethynyl-3-quinuclidinol; 3-(4-benzyl-2-pyrazyl-5-pyridyl)ethynyl-3-quinuclidinol; 3-[4-benzyl-2-(4-pyridyl)-5-pyridyl]ethynyl-3-quinuclidinol; 3-[4-benzyl-2-(2-methoxyethoxy)-5-pyridyl]ethynyl-3-quinuclidinol; 3-[2-benzyl-6-(4-ethoxycarbonylpiperidino)-3-pyridyl]ethynyl-3-quinuclidinol; 3-(2-benzyl-6-morpholino-3-pyridyl)ethynyl-3-quinuclidinol; 3-[2-benzyl-6-(4-methoxypiperidino)-3-pyridyl]ethynyl-3-quinuclidinol; (3R)-3-[2-benzyl-6-(2-methoxyethyl)oxy-3-pyridyl]ethynyl-3-quinuclidinol; (3R)-3-[2-benzyl-6-(3-methoxypropyl)oxy-3-pyridyl]ethynyl-3-quinuclidinol; (3S)-3-[2-benzyl-6-(3-methoxypropyl)oxy-3-pyridyl]ethynyl-3-quinuclidinol; (3R)-3-[2-benzyl-6-(3-fluoropropyl)oxy-3-pyridyl]ethynyl-3-quinuclidinol; (3R)-3-[2-benzyl-6-(1,3-dioxolan-2-yl)methyloxy-3-pyridyl]ethynyl-3-quinuclidinol; (3R)-3-[2-benzyl-6-(3-hydroxypropyl)oxy-3-pyridyl]ethynyl-3-quinuclidinol; 3-[2-benzyl-6-[3-(3-methoxycarbonylpropanoyloxy)propyl]oxy-3-pyridyl]ethynyl-3-quinuclidinol; 3-[2-benzyl-6-[3-[N-(tert-butoxycarbonyl)alanyloxy]propyl]oxy-3-pyridyl]ethynyl-3-quinuclidinol; (3R)-3-[4-benzyl-2-(3-pyridyl)-5-pyridyl]ethynyl-3-quinuclidinol; (3R)-3-[4-benzyl-2-(2-pyridyl)-5-pyridyl]ethynyl-3-quinuclidinol; (3R)-3-[4-benzyl-2-(3,4-methylenedioxyphenyl)-5-pyridyl]ethynyl-3-quinuclidinol; (3R)-3-[2-benzyl-6-[(3R,4S)-3-hydroxy-4-methoxypyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol; (3R)-3-[2-benzyl-6-[(3S,4R)-3-fluoro-4-methoxypyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol; (3R)-3-[2-benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol; (3R)-3-[2-benzyl-6-[(3R,4R)-3,4-dimethoxypyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol; (3R)-3-[2-benzyl-5-chloro-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol; (3R)-3-[2-benzyl-5-bromo-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol; (3R)-3-[2-benzyl-6-(3,3-ethylenedioxypyrrolidine-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol; (3R)-3-[2-benzyl-5-chloro-6-(3,3-ethylenedioxypyrrolidine-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol; (3R)-3-[2-benzyl-6-(cis-3,4-dimethoxypyrrolidine-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol; (3R)-3-[2-benzyl-6-[(3R,4R)-3,4-dimethoxy-2-pyrrolidinone-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol; (3R)-3-[2-benzyl-6-[(3R,4R)-4-hydroxy-3-methoxy-2-pyrrolidinone-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol; (3R)-3-[2-benzyl-6-(3,3-ethylenedioxy-2-pyrrolidinone-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol; (3R)-3-[2-benzyl-6-[(3R)-3-hydroxy-2-pyrrolidinone-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol; (3R)-3-[2-benzyl-6-[(3R)-3-methoxy-2-pyrrolidinone-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol; (3R)-3-[4-benzyl-2-(1,4-dioxene-2-yl)-5-pyridyl]ethynyl-3-quinuclidinol; and (3R)-3-[4-benzyl-2-[(3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-yl]-3-pyrimidyl]ethynyl-3-quinuclidinol,
(20) a squalene synthesizing enzyme inhibitor comprising the compound described in any of (1) to (19), a salt thereof or a hydrate of them,
(21) a medicinal composition comprising a compound (I) represented by the following formula: 
(in which R1 represents (1) hydrogen atom or (2) hydroxyl group; HAr represents an aromatic heterocycle which may be substituted with 1 to 3 groups; Ar represents an optionally substituted aromatic ring; W represents a chain represented by (1) xe2x80x94CH2xe2x80x94CH2xe2x80x94 which may be substituted, (2) xe2x80x94CHxe2x95x90CHxe2x80x94 which may be substituted, (3) xe2x80x94Cxe2x89xa1Cxe2x80x94, (4) xe2x80x94NHxe2x80x94COxe2x80x94, (5) xe2x80x94COxe2x80x94NHxe2x80x94, (6) xe2x80x94NHxe2x80x94CH2xe2x80x94, (7) xe2x80x94CH2xe2x80x94NHxe2x80x94, (8) xe2x80x94CH2xe2x80x94COxe2x80x94, (9) xe2x80x94COxe2x80x94CH2xe2x80x94, (10) xe2x80x94NHxe2x80x94S(O)lxe2x80x94, (11) xe2x80x94S(O)lxe2x80x94NHxe2x80x94, (12) xe2x80x94CH2xe2x80x94S(O)lxe2x80x94 or (13) xe2x80x94S(O)lxe2x80x94CH2xe2x80x94 (l denotes 0, 1 or 2); and X represents a chain represented by (1) a single bond, (2) an optionally substituted C1-6 alkylene chain, (3) an optionally substituted C2-6 alkenylene chain, (4) an optionally substituted C2-6 alkynylene chain, (5) a formula xe2x80x94Qxe2x80x94 (wherein Q represents oxygen atom, sulfur atom, CO or N(R2) (wherein R2 represents a C1-6 alkyl group or a C1-6 alkoxy group)), (6) xe2x80x94NHxe2x80x94COxe2x80x94, (7) xe2x80x94COxe2x80x94NHxe2x80x94, (8) xe2x80x94NHxe2x80x94CH2xe2x80x94, (9) xe2x80x94CH2xe2x80x94NHxe2x80x94, (10) xe2x80x94CH2xe2x80x94COxe2x80x94, (11) xe2x80x94COxe2x80x94CH2xe2x80x94, (12) xe2x80x94NHxe2x80x94S(O)mxe2x80x94, (13) xe2x80x94S(O)mxe2x80x94NHxe2x80x94, (14) xe2x80x94CH2xe2x80x94S(O)mxe2x80x94, (15) xe2x80x94S(O)mxe2x80x94CH2xe2x80x94 (wherein m denotes 0, 1 or 2) or (16) xe2x80x94(CH2)nxe2x80x94Oxe2x80x94 (wherein n denotes an integer from 1 to 6)), a salt thereof or a hydrate of them,
(22) the medicinal composition described in (21), which is a preventive or curative agent for a disease against which squalene synthesizing enzyme inhibition is efficacious,
(23) the medicinal composition described in (21), which is a cholesterol biosynthesis inhibitor,
(24) the medicinal composition described in (21), which is a triglyceride biosynthesis inhibitor,
(25) the medicinal composition described in (21), which is an agent for preventing or curing hyper lipidemia,
(26) the medicinal composition described in (21), which is an agent for preventing or curing arterial sclerosis diseases or ischemic heart diseases,
(27) the medicinal composition described in (21), which is an agent for preventing or curing hypertension, coronary diseases, cerebrovascular diseases, aortic diseases, peripheral arterial diseases, angina pectoris, acute coronary syndromes or cardiac infarction,
(28) a method for producing a quinuclidine compound (IV) represented by the following formula: 
(in which A1, A2, A3, a, b and R1 have the same meanings as defined above), a salt thereof or a hydrate of them, which comprises the step of reacting an aromatic heterocyclic compound (II) represented by the following formula: 
(in which A1 and A3 are the same as or different from each other and each means 1) an optionally substituted carbon atom or 2) a hetero atom; A2 means 1) an optionally substituted carbon atom, 2) a hetero atom or 3) a single bond; L means a leaving group; and a and b are different from each other and each means 1) a group xe2x80x94Xxe2x80x94Ar (in which X represents a chain represented by (1) a single bond; (2) an optionally substituted C6 alkylene chain; (3) an optionally substituted C2-6 alkenylene chain; (4) an optionally substituted C2-6 alkynylene chain; (5) a formula xe2x80x94Qxe2x80x94 (wherein Q represents oxygen atom, sulfur atom, CO or N(R2) (wherein R2 represents a C1-6 alkyl group or a C1-6 alkoxy group)); (6) xe2x80x94NHxe2x80x94COxe2x80x94; (7) xe2x80x94COxe2x80x94NHxe2x80x94; (8) xe2x80x94NHxe2x80x94CH2xe2x80x94; (9) xe2x80x94CH2xe2x80x94NHxe2x80x94; (10) xe2x80x94CH2xe2x80x94COxe2x80x94; (11) xe2x80x94COxe2x80x94CH2xe2x80x94; (12) xe2x80x94NHxe2x80x94S(O)mxe2x80x94; (13) xe2x80x94S(O)mxe2x80x94NHxe2x80x94; (14) xe2x80x94CH2xe2x80x94S(O)mxe2x80x94; (15) xe2x80x94S(O)mxe2x80x94CH2xe2x80x94 (wherein m denotes 0, 1 or 2); or (16) xe2x80x94(CH2)nxe2x80x94Oxe2x80x94 (wherein n denotes an integer from 1 to 6); and Ar represents an optionally substituted aromatic ring, respectively), or 2) any one group selected from: (1) a halogen atom; (2) hydroxyl group; (3) thiol group; (4) nitro group; (5) nitrile group; (6) an optionally substituted linear C1-6 hydrocarbon group; (7) an optionally substituted C3-8 cyclic hydrocarbon group; (8) an optionally substituted C6-14 aromatic hydrocarbon cyclic group; (9) an optionally substituted 5- to 14-membered aromatic heterocyclic group; (10) an optionally substituted 4- to 10-membered non-aromatic heterocyclic group; (11) an optionally substituted C1-6 alkoxy group; (12) an optionally substituted C3-8 cycloalkyloxy group; (13) an optionally substituted linear C1-6 hydrocarbon-thio group; (14) an optionally substituted C3-8 cyclic hydrocarbon-thio group; (15) an optionally substituted C6-14 aromatic hydrocarbon-oxy group; (16) an optionally substituted 5- to 14-membered heterocyclic-oxy group; (17) an optionally substituted C6-14 aromatic hydrocarbon-thio group; (18) an optionally substituted 5- to 14-membered heterocyclic-thio group; (19) an optionally substituted amino group; (20) an azide group; (21) guanidino group; (22) carbamide group; (23) formyl group; (24) an optionally substituted C1-6 imidoyl group; (25) a substituted carbonyl group; (26) a substituted carbonyl-oxy group; (27) a carboxyl group which may form a salt; (28) an optionally substituted carbamoyl group; (29) an optionally substituted C1-4 alkylenedioxy group; (30) an optionally substituted sulfinyl group; and (31) an optionally substituted sulfonyl group, respectively) and a quinuclidine compound (III) represented by the following formula: 
(wherein R1 means hydrogen atom or hydroxyl group) in the presence of a Pd catalyst, a copper salt and a base,
(29) a method for producing a quinuclidine compound (VI) represented by the following formula: 
(in which A1, A2, A3, a, Ar and R1 have the same meanings as defined above), a salt thereof or a hydrate of them, which comprises the step of reacting a quinuclidine compound (V) represented by the following formula: 
(in which A1 and A3 are the same as or different from each other and each means 1) an optionally substituted carbon atom or 2) a hetero atom; A2 represent 1) an optionally substituted carbon atom, 2) a hetero atom or 3) a single bond; L means a leaving group; a means a group xe2x80x94Xxe2x80x94Ar (wherein X and Ar have the same meanings as defined above); and R1 means hydrogen atom or hydroxyl group, respectively) and an aromatic cyclic compound represented by the following formula:
Arxe2x80x94M
(in which Ar means an optionally substituted aromatic ring; and M means an optionally substituted metal atom, respectively) in the presence of a Pd catalyst, and
(30) a method for producing a quinuclidine compound (VIII) represented by the following formula: 
(in which A1, A2, A3, a, Ar and R1 have the same meanings as defined above), a salt thereof or a hydrate of them, which comprises the step of reacting a quinuclidine compound (VII) represented by the following formula: 
(in which A1 and A3 are the same as or different from each other and each means 1) an optionally substituted carbon atom or 2) a hetero atom; A2 means 1) an optionally substituted carbon atom, 2) a hetero atom or 3) a single bond; M means an optionally substituted metal atom; a means 1) a group xe2x80x94Xxe2x80x94Ar (wherein X and Ar have the same meanings as defined above); and R1 means hydrogen atom or hydroxyl group, respectively) and an aromatic cyclic compound represented by the following fromula:
Arxe2x80x94L
(in which Ar means an optionally substituted aromatic ring; and L means a leaving group, respectively) in the presence of a Pd catalyst. Also, the present invention provides a method of preventing and curing a disease on which squalene synthesizing enzyme inhibition is effective by administering the compound represented by the above formula (I), its salt or hydrates of these compounds to a patient in a pharmacologically effective amount and a use of the compound represented by the above formula (I), its salt or hydrates thereof for producing a preventive and curing agent for a disease on which squalene synthesizing enzyme inhibition is effective.
In the specification of the present invention, there is the case where the structural formula of a compound represents a definite isomer. However, the present invention includes isomers such as geometrical isomers, optical isomers based on asymmetric carbon, stereoisomers and tautomers and is not limited by the description of the formula illustrated for the sake of convenience.
The definitions of the terms used in the specification of the present invention will be explained below.
In the specification of the present invention, the group represented by R1 in the above formula (I) means hydrogen atom or hydroxyl group and preferably hydroxyl group.
In the specification of the present invention, the xe2x80x9caromatic heterocycle which may be substituted with 1 to 3 groupsxe2x80x9d represented by HAr in the aforementioned formula (I) is preferably, for example, a 5- to 14-membered aromatic heterocycle which has 1 to 4 atoms selected optionally from nitrogen atom, sulfur atom and oxygen atom and may be substituted with 1, 2 or 3 substituents, and more preferably, an aromatic heterocycle which may be substituted with 1 to 3 groups selected from (1) halogen atom, (2) hydroxyl group, (3) thiol group, (4) nitro group, (5) nitrile group, (6) a C1-6 chain hydrocarbon group which may be substituted, (7) a C3-8 cyclic hydrocarbon group which may be substituted, (8) a C6-14 aromatic hydrocarbon cyclic group which may be substituted, (9) a 5- to 14-membered aromatic heterocyclic group which may be substituted, (10) a 4- to 10-membered non-aromatic heterocyclic group which may be substituted, (11) a C1-6 alkoxy group which may be substituted, (12) a C3-8 cycloalkoxy group which may be substituted, (13) a C1-6 chain hydrocarbon-thio group which may be substituted, (14) a C3-8 cyclic hydrocarbon-thio group which may be substituted, (15) a C6-14 aromatic hydrocarbon-oxy group which may be substituted, (16) a 5- to 14-membered heterocycle-oxy group which may be substituted, (17) a C6-14 aromatic hydrocarbon-thio group which may be substituted, (18) a 5- to 14-membered heterocycle-thio group which may be substituted, (19) an amino group which may be substituted, (20) azide group, (21) guanidino group, (22) carbamide group, (23) formyl group, (24) a C1-6 imidoyl group which maybe substituted, (25) a carbonyl group which is substituted, (26) a carbonyl-oxy group which is substituted, (27) a carboxy group which may form a salt, (28) a carbamoyl group which may be substituted, (29) a C1-4 alkylenedioxy group which may be substituted, (30) a sulfinyl group which may be substituted and (31) a sulfonyl group which may be substituted.
In the above-mentioned definition of HAr, the xe2x80x9caromatic heterocyclexe2x80x9d means monocyclic type, dicyclic type or tricyclic type aromatic heterocycles. Examples thereof include 5- to 14-membered aromatic heterocyclic groups containing 1 to 4 atoms selected from nitrogen atom, sulfur atom and oxygen atom. Specifically, aromatic heterocycles containing two or more different atoms selected from nitrogen atom, sulfur atom and oxygen atom, such as nitrogen-containing aromatic heterocycles, e.g., pyrrole ring, pyridine ring, pyridone ring, pyridazine ring, pyrimidine ring, pyrazine ring, pyrazole ring, imidazole ring, indole ring, isoindolyl ring, indolizine ring, purine ring, indazole ring, quinoline ring, isoquinoline ring, quinolizine ring, phthalazine ring, naphthyridine ring, quinoxaline ring, quinazoline ring, cinnoline ring, pteridine ring, imidazotriazine ring, pyrazinopyridazine ring, acridine ring, phenanthridine ring, carbazole ring, carbazoline ring, perimidine ring, phenanthroline ring and phenarsine ring; sulfur-containing aromatic heterocycles, e.g., a thiophene ring and benzothiophene ring; oxygen-containing aromatic heterocycles, e.g., a furan ring, pyran ring, cyclopentapyran ring, benzofuran ring, isobenzofuran ring; thiazole ring, isothiazole ring, benzthiazole ring, benzthiadiazole ring, phenothiazine ring, isoxazole ring, furazane ring, phenoxazine ring, pyrazoloxazole ring, imidazothiazole ring, thienofuran ring, furopyrrole ring and pyridoxazine ring. As preferable examples thereof pyrrole ring, pyridine ring, pyridone ring, pyrimidine ring, imidazole ring, indole ring, quinoline ring, isoquinoline ring, quinolizine ring, phthalazine ring, naphthyridine ring, quinazoline ring, acridine ring, phenarsine ring, thiophene ring, benzothiophene ring, furan ring, pyran ring, benzofuran ring, thiazole ring, benzthiazole ring and phenothiazine ring are given. As more preferable examples thereof, pyrrole ring, pyridine ring, thiophene ring, benzothiophene ring, thiazole ring and benzthiazole ring are given.
In the above definition, the xe2x80x9chalogen atomxe2x80x9d means halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom and is preferably fluorine atom, chlorine atom and bromine atom.
The xe2x80x9cC1-6 chain hydrocarbon groupxe2x80x9d in the xe2x80x9cC1-6 chain hydrocarbon group which may be substitutedxe2x80x9d given as the substituent of HAr means xe2x80x9ca C1-6 alkyl groupxe2x80x9d, xe2x80x9ca C2-6 alkenyl groupxe2x80x9d and xe2x80x9ca C2-6 alkynyl groupxe2x80x9d. As the xe2x80x9cC1-6 alkyl groupxe2x80x9d, for example, straight-chain or branched C1-6 alkyl groups such as methyl group, ethyl group, n-propyl group, i-propyl group, sec-propyl group, n-butyl group, i-butyl group, sec-butyl group, t-butyl group, n-pentyl group, i-pentyl group, sec-pentyl group, t-pentyl group, n-hexyl group, i-hexyl group, 1,2-dimethylpropyl group, 2-ethylpropyl group, 1-methyl-2-ethylpropyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,1,2-triethylpropyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 2-ethylbutyl group, 1,3-dimethylbutyl group, 2-methylpentyl group and 3-methylpentyl group are preferable. As the xe2x80x9cC2-6 alkenyl groupxe2x80x9d, straight-chain or branched C2-6 alkenyl groups such as vinyl group, allyl group, isopropenyl group, 1-propene-2-yl group, 1-butene-1-yl group, 1-butene-2-yl group, 1-butene-3-yl group, 2-butene-1-yl group and 2-butene-2-yl group are preferable. As the xe2x80x9cC2-6 alkynyl groupxe2x80x9d, ethynyl group, propynyl group, butynyl group, pentynyl group and hexynyl group are preferable. Also, the term xe2x80x9cmay be substitutedxe2x80x9d implies that may be substituted with one or two groups selected from, for example, (1) a hydroxyl group which may be protected, (2) halogen atom, (3) nitrile group, (4) carboxyl group, (5) a C3-8 cycloalkyl group, C3-8 cycloalkenyl group or C3-8 cycloalkynyl group, which may be hydroxylated or halogenated, (6) a C1-6 alkoxy group which may be substituted with a group selected from a halogen atom, hydroxyl group, a C6-14 aryl group, 5- to 14-membered heteroaryl group and a C6-14 aryl-C1-6 alkoxy group, (7) a C3-8 cycloalkyloxy group which may be halogenated or hydroxylated, (8) a C3-8 cycloalkenyloxy group which may be halogenated or hydroxylated, (9) a C1-6 alkoxy-carbonyl group, (10) a C1-4 alkylenedioxy group which may be halogenated, (11) a C1-6 alkanoyl group which may be substituted with a group selected from hydroxyl group, a C1-6 alkoxy group and a C1-6 alkanoyloxy group, (12) a C6-14 aryl group which may be substituted with a group selected from a halogen atom, a C1-6 alkyl group and a C1-6 alkoxy group, (13) a 5- to 14-membered aromatic heterocyclic group which may be substituted with a group selected from a halogen atom, a C1-6 alkyl group, a C3-8 alkenyl group, a C3-8 alkynyl group and a C1-6 alkoxy group, (14) a 4- to 10-membered non-aromatic heterocyclic group which may be substituted with a group selected from a halogen atom, a C1-6 alkyl group, a C3-8 alkenyl group, a C3-8 alkynyl group and a C1-6 alkoxy group, (15) a group (EtO)2POxe2x80x94, (16) acetyl group, (17) a sulfonyl group which may be substituted with a group selected from a C1-6 hydrocarbon group, a mino-(C1-6 hydrocarbon)-amino group and a di-(C1-6 hydrocarbon)-amino group, (18) an amino group which may be substituted with C1-6 hydrocarbon group, (19) a C1-6 hydrocarbon group-thio group which may be hydroxylated or halogenated and (20) a carbamoyl group which may be substituted with a C1-6 hydrocarbon group.
The xe2x80x9cC1-6 chain hydrocarbon group which may be substitutedxe2x80x9d is preferably a C1-6 chain hydrocarbon groups which may substituted with one or two groups selected from (1) hydroxyl group, (2) a halogen atom, (3) nitrile group, (4) a C1-6 cycloalkyl group, (5) a C1-6 alkoxy group, (6) a C1-6 alkoxy-C1-6 alkoxy group, (7) a C1-4 alkylenedioxy group, (8) a C1-6 alkoxy-carbonyl group, (9) a C1-6 alkanoyl group, (10) a C1-6 alkoxy-C1-6 alkanoyl group, (11) a C1-6 alkanoyl-oxy group, (12) a C1-6 alkanoyl-oxy-C1-6 alkanoyl group, (13) a 5- to 14-membered heterocyclic group, (14) a 5- to 10-membered condensed heterocyclic group which may substituted with a C1-6 alkoxy group, (15) carboxyl group, (16) (EtO)2POxe2x80x94 and (17) a C1-6 alkyl-sulfonyl group, and more preferably a substituted C1-6 chain hydrocarbon group such as (1) unsubstituted C1-6 chain hydrocarbon groups such as ethyl group, propyl group and 2-propene-1-yl group, (2) C1-6 chain hydrocarbon groups substituted with a C6-14 aromatic hydrocarbon group such as phenyl group, (3) C1-6 chain hydrocarbon groups substituted with a 5- to 14-membered aromatic heterocyclic group such as pyridyl group and (4) substituted C1-6 chain hydrocarbon groups such as a C1-6 alkoxy-C1-6 chain hydrocarbon group.
In the above-mentioned definition, for example, the xe2x80x9cC1-6 chain hydrocarbon group which may be halogenatedxe2x80x9d means that any one of the carbons of the xe2x80x9cC1-6 chain hydrocarbon groupxe2x80x9d may be substituted with a halogen atom. Specific examples thereof include trifluoromethyl group, 2-chloroethyl group, 1,2-dichloroethyl group, 2-bromoethyl group, 3-bromopropyl group, 3,3,3-trifluoropropyl group, 4-chlorobutyl group, 2,2-dimethyl-4-bromobutyl group and 3-chloro-2-propenyl group. Also, the xe2x80x9cC1-6 alkoxy group which may be halogenatedxe2x80x9d means that any one of the carbons of the xe2x80x9cC1-6 alkoxy groupxe2x80x9d may be substituted with a halogen atom. Specific examples thereof include trifluoromethoxy group, 2-chloroethoxy group, 1,2-dichloroethoxy group, 2-bromoethoxy group, 3-bromopropyloxy group, 3,3,3-trifluoropropyloxy group, 4-chlorobutyloxy group, and 2,2-dimethyl-4-bromobutyloxy group.
The xe2x80x9cC3-8 cyclic hydrocarbon groupxe2x80x9d in the xe2x80x9cC3-8 cyclic hydrocarbon group which may be substitutedxe2x80x9d which is given as the substituent of HAr means a xe2x80x9cC3-8 cycloalkyl groupxe2x80x9d, a xe2x80x9cC3-8 cycloalkenyl groupxe2x80x9d and the like. As the xe2x80x9cC3-8 cycloalkyl groupxe2x80x9d, 3- to 8-membered cycloalkyl groups such as cyclopropanyl group, cyclobutanyl group, cyclopentanyl group, cyclohexanyl group and cycloheptanyl group are preferable. As the xe2x80x9cC3-8 cycloalkenyl groupxe2x80x9d, 3- to 8-membered cycloalkenyl groups such as cyclopropenyl group, cyclobutenyl group, cyclopentenyl group, cyclohexenyl group and cycloheptenyl group are preferable. Also, the term xe2x80x9cmay be substitutedxe2x80x9d implies that the above xe2x80x9cC3-8 cyclic hydrocarbon groupxe2x80x9d may be substituted with one or two groups selected from, for example, (1) a hydroxyl group which may be protected, (2) a halogen atom, (3) nitrile group, (4) carboxy group, (5) a C1-6 alkyl group which may be substituted with a group selected from hydroxyl group, a halogen atom, a C1-6 alkoxy group which may be halogenated, a C1-6 hydrocarbon-thio group which may be halogenated, an amino group which may be substituted with a C1-6 hydrocarbon group and a C1-6 alkanoyl group, (6) a C1-6 alkenyl group which may be substituted with a group selected from hydroxyl group, a halogen atom, a C1-6 alkoxy group which may be halogenated, a C1-6 hydrocarbon-thio group which may be halogenated, an amino group which may be substituted with a C1-6 hydrocarbon group and a C1-6 alkanoyl group, (7) a C1-6 alkynyl group which may be substituted with a group selected from hydroxyl group, a halogen atom, a C1-6 alkoxy group which may be halogenated, a C1-6 hydrocarbon-thio group which may be halogenated, an amino group which may be substituted with a C1-6 hydrocarbon group and a C1-6 alkanoyl group, (8) an amino group which may be substituted with a group selected from hydroxyl group, a halogen atom, a C1-6 alkoxy group which may be halogenated, a C1-6 hydrocarbon-thio group which may be halogenated, a C1-6 alkanoyl group and a C1-6 hydrocarbon group, (9) a C1-6 alkoxy group which may be substituted with a group selected from hydroxyl group, a halogen atom, a C1-6 alkyl group which may be halogenated, a C1-6 alkoxy group which may be hydroxylated or halogenated, a C1-6 hydrocarbon-thio group which may be halogenated, an amino group which may be substituted with a C1-6 hydrocarbon group and a C1-6 alkanoyl group, (10) a C1-6 hydrocarbon-thio group which may be substituted with a group selected from hydroxyl group, a halogen atom, a C1-6 alkyl group which may be halogenated, a C1-6 alkenyl group which may be halogenated, a C1-6 alkynyl group which may be halogenated, a C1-6 alkoxy group which may be hydroxylated and halogenated, a C1-6 hydrocarbon-thio group which may be halogenated, an amino group which may be substituted with a C1-6 hydrocarbon group and a C1-6 alkanoyl group, (11) a C1-6 alkanoyl group which may be substituted with a group selected from hydroxyl group, a C1-6 alkoxy group and a C1-6 alkanoyloxy group, (12) a C6-14 aryl group which may be substituted with a group selected from a halogen atom, a C1-6 alkyl group and a C1-6 alkoxy group, (13) a 5- to 14-membered aromatic heterocyclic group which may be substituted with a halogen group, a C1-6 alkyl group, a C3-8 alkenyl group, a C3-8 alkynyl group and a C1-6 alkoxy group, (14) a non-aromatic heterocyclic group which may be substituted with a group selected from a halogen atom, a C1-6 alkyl group, a C3-8 alkenyl group, a C3-8 alkynyl group and a C1-6 alkoxy group, (15) a C1-6 alkoxy-carbonyl group, (16) a C1-4 alkylenedioxy group which may be halogenated, (17) the formula (EtO)2POxe2x80x94 and (18) acetyl group.
It is to be noted that in the specification of the present invention, the xe2x80x9chydrocarbon groupxe2x80x9d shown in the formula (I) implies both of the xe2x80x9cC1-6 chain hydrocarbon groupxe2x80x9d and the xe2x80x9cC3-8 cyclic hydrocarbon groupxe2x80x9d which have the same definitions as above.
Preferable examples of the xe2x80x9cC6-14 aromatic hydrocarbon cyclic groupxe2x80x9d in the xe2x80x9cC6-14 aromatic hydrocarbon cyclic group which may be substitutedxe2x80x9d which is given as the substituent of HAr include phenyl group, pentalenyl group, indenyl group, naphthyl group, azulenyl group, heptalenyl group, benzocyclooctenyl group and phenanthrenyl group. Among these groups, a phenyl group and naphthyl group are more preferable. Also, the term xe2x80x9cmay be substitutedxe2x80x9d implies that the above xe2x80x9cC6-14 aromatic hydrocarbon cyclic groupxe2x80x9d may be substituted with one or more groups selected from, for example, (1) hydroxyl group, (2) a halogen atom, (3) a C1-6 alkyl-sulfonyl group, a C1-6 alkenyl-sulfonyl group or a C1-6 alkynyl-sulfonyl group which may be halogenated, (4) a C1-4 alkylenedioxy group which may be halogenated, (5) a C1-6 alkoxy group which may be halogenated, (6) a C1-6 hydrocarbon-thio group which may be halogenated, (7) a C1-6 alkoxy-carbonyl group, (8) a C6-14 aryl-C1-6 alkoxy group, (9) a C1-7 alkanoylamino group, (10) a C1-6 alkyl-carbamoyl group, (11) a C1-6 alkenyl-carbamoyl group, (12) a C1-6 alkynyl-carbamoyl group and (13) an amino group which may be substituted with a C1-6 hydrocarbon group. Preferable examples of the xe2x80x9cC6-14 aromatic hydrocarbon cyclic group which is substitutedxe2x80x9d include phenyl groups converted into nitriles, halogenated phenyl group, phenyl group substituted with a C1-6 alkyl group such as an ethyl group, phenyl group substituted with a C1-6 alkoxy group such as methoxy group, phenyl group substituted with an alkylenedioxy group such as 2,4-methylenedioxy group and phenyl group substituted with a di-(C1-6 alkyl)-amino group such as dimethylamino group.
It is to be noted that, in the present invention, the xe2x80x9cC6-14 aryl groupxe2x80x9d shown in the formula (I) has the same meaning as the above-mentioned xe2x80x9cC6-14 aromatic hydrocarbon cyclic groupxe2x80x9d and excludes aromatic heterocyclic groups.
The xe2x80x9c5- to 14-membered aromatic heterocyclic groupxe2x80x9d in the xe2x80x9c5- to 14-membered aromatic heterocyclic group which may be substitutedxe2x80x9d which is given as the substituent of HAr means an aromatic heterocycle having 1 to 4 atoms selected from nitrogen atom, oxygen atom and sulfur atom. Specific examples thereof include pyrrolyl group, pyridinyl group, pyridazinyl group, pyrimidinyl group, pirazinyl group, thiazolyl group and oxazolyl group. Also, the term xe2x80x9cmay be substitutedxe2x80x9d means that the above-mentioned xe2x80x9c5- to 14-membered aromatic heterocyclic groupxe2x80x9d may be substituted with one or more groups selected from (1) hydroxyl group, (2) a halogen atom, (3) nitrile group, (4) a C1-6 alkyl group, C1-6 alkenyl group or C1-6 alkynyl group, which may be halogenated, (5) a C1-6 alkoxy group which may be halogenated, (6) a C1-6 alkyl-thio group, C1-6 alkenyl-thio group or C1-6 alkynyl-thio group, which may be halogenated, (7) a C1-6 alkoxy-C1-6 alkyl group, (8) acetyl group, (9) a C1-6 alkanoyl group, (10) a mono-(C1-6 hydrocarbon)-amino group, (11) a di-(C1-6 hydrocarbon)-amino group and (12) a tri-(C1-6 hydrocarbon)-amino group. Preferable examples of the xe2x80x9csubstituted 5- to 14-membered aromatic heterocyclic groupxe2x80x9d include aromatic heterocycles converted to nitrites, aromatic heterocycles substituted with a C1-6 alkyl group, aromatic heterocycles substituted with a C1-6 alkoxy group, aromatic heterocycles substituted with a C1-6 alkoxy-C1-6 alkyl group, aromatic heterocycles substituted with a mono-(C1-6 alkyl)-amino group and aromatic heterocycles substituted with a di-(C1-6 alkyl)-amino group.
In the specification of the present invention, the xe2x80x9cC6-14 heteroaryl groupxe2x80x9d shown in the formula (I) has the same meaning as the above-mentioned xe2x80x9c5- to 14-membered aromatic heterocyclic groupxe2x80x9d.
It is to be noted that in the specification of the present invention, the xe2x80x9caromatic ringxe2x80x9d shown in the formula (I) implies all rings having the same meanings as the above-mentioned xe2x80x9cC6-14 aromatic hydrocarbon ringxe2x80x9d and xe2x80x9c5- to 14-membered aromatic heterocyclic groupxe2x80x9d.
The xe2x80x9c4- to 10-membered non-aromatic heterocyclic groupxe2x80x9d in the xe2x80x9c4- to 10-membered non-aromatic heterocyclic group which may be substitutedxe2x80x9d which is given as the substituent of HAr means a ring which has the same meaning as the aforementioned xe2x80x9cC3-8 cyclic hydrocarbon groupxe2x80x9d and in which 1 to 4 carbon atoms are substituted with an atom selected from nitrogen atom, oxygen atom and sulfur atom and also means that it includes a unsaturated condensed ring. Preferable specific examples thereof include pyrrolidinyl group, pyrrolinyl group, piperidinyl group, piperazinyl group, imidazolinyl group, pyrazolidinyl group, imidazolydinyl group, morpholinyl group, tetrahydropyranyl group, azetidinyl group, oxetanyl group, oxathiolanyl group, phthalimide and succinimide. More preferable examples include pyrrolidinyl group, piperidinyl group and morpholinyl group. Also, the term xe2x80x9cmay be substitutedxe2x80x9d means that the above-mentioned xe2x80x9c4- to 10-membered aromatic heterocyclic groupxe2x80x9d may be substituted with one or more groups selected from (1) hydroxyl group, (2) a halogen atom, (3) nitrile group, (4) a C1-6 alkyl group, C1-6 alkenyl group or C1-6 alkynyl group which may be halogenated, (5) a C1-6 alkoxy group which may be halogenated, (6) a C1-6 alkyl-thio group, C1-6 alkenyl-thio group or C1-6 alkynyl-thio group which may be halogenated, (7) a C1-6 alkoxy-C1-6 alkyl group, (8) acetyl group, (9) a C1-6 alkanoyl group, (10) a mono-(C1-6 hydrocarbon)-amino group, (11) a di-(C1-6 hydrocarbon)-amino group, (12) a tri-(C1-6 hydrocarbon group-amino group and (13) an oxo group forming carbonyl group, N-oxide group, sulfoxide group or sulfonic group.
It is to be noted that in the specification of the present invention, the xe2x80x9cheterocyclexe2x80x9d shown in the formula (I) implies both of the xe2x80x9c5- to 14-membered heterocyclic groupxe2x80x9d and the xe2x80x9c4- to 10-membered non-aromatic heterocyclic groupxe2x80x9d which have the same definitions as above.
The xe2x80x9cC1-6 alkoxy groupxe2x80x9d in the xe2x80x9cC1-6 alkoxy group which may be substitutedxe2x80x9d given as the substituent of HAr means the xe2x80x9calkoxy groupxe2x80x9d corresponding to the xe2x80x9cC1-6 chain hydrocarbon groupxe2x80x9d in the aforementioned definition. Preferable examples thereof include C1-6 alkyl-oxy groups such as methoxy group, ethoxyl group, n-propoxy group, i-propoxy group, sec-propoxy group, n-butoxy group, i-butoxy group, sec-butoxy group, t-butoxy group, n-pentoxy group, i-pentoxy group, sec-pentoxy group, t-pentoxy group, n-hexoxy group, i-hexoxy group, 1,2-dimethylpropoxy group, 2-ethylpropoxy group, 1-methyl-2-ethylpropoxy group, 1-ethyl-2-methylpropoxy group, 1,1,2-trimethylpropoxy group, 1,1-dimethylbutoxy group, 2,2-dimethylbutoxy group, 2-ethylbutoxy group, 1,3-dimethylbutoxy group, 2-methylpentoxy group and 3-methylpentoxy group; C2-6 alkenyl-oxy groups such as vinyloxy group, allyloxy group, isopropoxyl group, 1-propenyl-2-oxy group, 1-butenyl-1-oxy group, 1-butenyl-2-oxy group, 1-butenyl-3-oxy group, 2-butenyl-1-oxy group and 2-butenyl-2-oxy group; and C2-6 alkynyl-oxy groups such as ethynyloxy group, propinyloxy group, butynyloxy group, pentynyloxy group and hexynyloxy group. The term xe2x80x9cmay be substitutedxe2x80x9d means that may be substituted with one or more groups selected from, for example, (1) hydroxyl group, (2) a halogen atom, (3) a C1-6 alkyl group, C2-6 alkenyl group or C2-6 alkynyl group, which may be substituted with a group selected from hydroxyl group, a halogen atom, a 5- to 14-membered aromatic heterocyclic group and a 4- to 10-membered non-aromatic heterocyclic group, (4) a C3-8 cycloalkyl group or C3-8 cycloalkenyl group, which may be hydroxylated or halogenated, (5) a C1-6 alkoxy group which may be hydroxylated or halogenated, (6) a C1-6 alkylthio group, C1-6 alkenylthio group or C1-6 alkynylthio group, which may be halogenated, (7) a C3-8 cycloalkyloxy group, C3-8 cycloalkenyloxy group or C3-8 cycloalkynyloxy group which may be halogenated, (8) a C3-8 cycloalkylthio group, C3-8 cycloalkenylthio group or C3-8 cycloalkynylthio group, which may be halogenated, (9) a C6-14 aryl group, (10) a C1-6 alkanoyl group which may be halogenated, (11) a 5- to 14-membered aromatic heterocyclic group and (12) a 4- to 10-membered non-aromatic heterocycle. Preferable examples of the xe2x80x9cC1-6 alkoxy group which is substitutedxe2x80x9d include a C1-6 alkoxy group which is hydroxylated, a C1-6 alkoxy group which is halogenated, a C1-6 alkoxy group substituted with a hydroxy-C3-8 cycloalkyl group, a C1-6 alkoxy group substituted with a non-aromatic heterocycle-oxy group, a C1-6 alkoxy-C1-6 alkoxy group, a C1-6 alkoxy group substituted with a C1-6 alkoxy-carbonyl group, a C1-6 alkoxy group substituted with a non-aromatic heterocyclic group and a C1-6 alkoxy group which is formyl-aminated.
The xe2x80x9cC3-8 cycloalkoxy groupxe2x80x9d in the xe2x80x9cC3-8 cycloalkoxy group which may be substitutedxe2x80x9d given as the substituent of HAr means the xe2x80x9ccycloalkoxy groupxe2x80x9d corresponding to the xe2x80x9cC1-6 cyclic hydrocarbon groupxe2x80x9d in the above definition. Preferable examples thereof include C3-8 cycloalkyloxy groups such as cyclopropyloxy group, cyclobutyoxy group, cyclopentyloxy group and cyclohexyloxy group and C3-8 cycloalkenyloxy groups such as cyclopropenyloxy group, cyclobutenyloxy group, cyclopentenyloxy group and cyclohexenyloxy group. Also, the term xe2x80x9cmay be substitutedxe2x80x9d means that the above-mentioned C3-8 alkoxy group may be substituted with one or two groups selected from, for example, (1) hydroxyl group, (2) a halogen atom, (3) a C1-6 hydrocarbon group which may be substituted with a group selected from hydroxyl group, a halogen atom, a C1-6 alkoxy group and a C1-6 alkanoyl group, (4) a C1-6 alkoxy group which may be substituted with a group selected from a halogen atom, a C1-6 alkoxy group and a C1-6 alkanoyl group and (5) a C1-6 hydrocarbon-thio group which may be substituted with a group selected from a halogen atom, a C1-6 alkoxy group and a C1-6 alkanoyl group. A C3-8 cycloalkoxy group which may be substituted with a C1-6 alkoxy group and the like are preferable.
The xe2x80x9cC1-6 chain hydrocarbon-thio groupxe2x80x9d in the xe2x80x9cC1-6 chain hydrocarbon-thio group which may be substitutedxe2x80x9d given as the substituent of HAr means the xe2x80x9cC1-6 chain hydrocarbon-thio groupxe2x80x9d corresponding to the xe2x80x9cC1-6 chain hydrocarbon groupxe2x80x9d in the above definition, that is, a xe2x80x9cC1-6 alkyl-thio groupxe2x80x9d, xe2x80x9cC1-6 alkenyl-thio groupxe2x80x9d and xe2x80x9cC1-6 alkynyl-thio groupxe2x80x9d. Specific examples thereof include methylthio group, ethylthio group, n-propylthio group, i-propylthio group, sec-propylthio group, n-butylthio group, i-butylthio group, sec-butylthio group, t-butylthio group, 1,2-dimethylpropylthio group, 2-ethylpropylthio group, 1,1-dimethylbutylthio group, 2,2-dimethylbutylthio group, 2-tylbutylthio group, 1,3-dimethylbutylthio group, isopropenylthio group, ethynylthio group and propinylthio group. Also, the term xe2x80x9cmay be substitutedxe2x80x9d implies that may be substituted with one or two groups selected from, for example, (1) hydroxyl group, (2) a halogen atom, (3) a C1-6 alkyl group, C1-6 alkenyl group or C1-6 alkynyl group, which may be substituted with a group selected from hydroxyl group, a halogen atom, a 5- to 14-membered aromatic heterocyclic group and a 4- to 10-membered non-aromatic heterocyclic group, (4) a C3-8 cycloalkyl group, C3-8 cycloalkenyl group or C3-8 cycloalkynyl group, which may be hydroxylated or halogenated, (5) a C1-6 alkoxy group which may be hydroxylated or halogenated, (6) a C1-6 alkylthio group, C1-6 alkenylthio group or C1-6alkynylthio group, which may be halogenated, (7) a C3-8 cycloalkyloxy group, C3-8 cycloalkenyloxy group or C3-8 cycloalkynyloxy group which may be halogenated, (8) a C3-8 cycloalkylthio group, C3-8 cycloalkenylthio group or C3-8 cycloalkynylthio group, which may be halogenated, (9) a C6-14 aryl group, (10) a C1-6 alkanoyl group which may be halogenated, (11) a 5- to 14-membered aromatic heterocyclic group and (12) a 4- to 10-membered non-aromatic heterocyclic group. The xe2x80x9cC1-6 chain hydrocarbon-thio group which may be substitutedxe2x80x9d is preferably a C1-6 chain hydrocarbon-thio group which may be hydroxylated, a C1-6 chain hydrocarbon-thio group which may be substituted with a C1-6 alkoxy group and the like.
The xe2x80x9cC3-8 cyclic hydrocarbon-thio groupxe2x80x9d in the xe2x80x9cC3-8 cyclic hydrocarbon-thio group which may be substitutedxe2x80x9d given as the substituent to HAr means the xe2x80x9cC1-6 cyclic hydrocarbon-thio groupxe2x80x9d corresponding to the xe2x80x9cC1-6 cyclic hydrocarbon groupxe2x80x9d in the above definition, that is, a xe2x80x9cC1-6 cycloalkyl-thio groupxe2x80x9d and xe2x80x9cC1-6 cyclic alkenyl-thio groupxe2x80x9d. Specific examples thereof include cyclopropanylthio group, cyclobutanylthio group, cyclohexanylthio group, cyclopropenylthio group, cyclobutenylthio group, cyclopentenylthio group and cyclohexenylthio group. The xe2x80x9cC3-8 cyclic hydrocarbon-thio group which may be substitutedxe2x80x9d is preferably a xe2x80x9cC3-8 cyclic hydrocarbon-thio groupxe2x80x9d substituted with one or two groups selected from (1) hydroxyl group, (2) a halogen atom, (3) a C3-8 alkyl group, C3-8 alkenyl group or C3-8 alkynyl group, which may be halogenated, (4) a C1-6 alkoxy group which may be halogenated, (5) a C1-6 hydrocarbon-thio group which may be halogenated and (6) a C1-6 alkanoyl group which may be halogenated.
The xe2x80x9cC6-14 aromatic hydrocarbon-oxy groupxe2x80x9d in the xe2x80x9cC6-14 aromatic hydrocarbon-oxy group which may be substitutedxe2x80x9d given as the substituent of HAr means the xe2x80x9cC1-6 cyclic hydrocarbon-oxy groupxe2x80x9d corresponding to the xe2x80x9cC6-14 aromatic hydrocarbon groupxe2x80x9d in the above definition. For example, phenyloxy group, pentalenyloxy group and naphthyloxy group are preferable. As the xe2x80x9cC6-14 aromatic hydrocarbon-oxy group which may be substitutedxe2x80x9d, a xe2x80x9cC6-14 aromatic hydrocarbon-oxy groupxe2x80x9d which is substituted with one or more groups selected from (1) hydroxyl group, (2) a halogen atom, (3) a C1-6 alkyl-sulfonyl group, C1-6 alkenyl-sulfonyl group or C1-6 alkynyl-sulfonyl group, which may be halogenated, (4) a C1-4 alkylenedioxy group which may be halogenated, (5) a C1-6 alkoxy group which may be halogenated, (6) a C1-6 hydrocarbon-thio group which may be halogenated, (7) a C1-6 alkoxy-carbonyl group, (8) C6-14 aryl-C1-6 alkoxy group, (9) a C1-7 alkanoylamino group, (10) a C1-6 alkyl-carbamoyl group, (11) a C1-6 alkenyl-carbamoyl group, (12) a C1-6 alkynyl-carbamoyl group and (13) an amino group which may be substituted with a C1-6 hydrocarbon group is preferable.
It is to be noted that in the specification of the present invention, the xe2x80x9cC6-14 aryloxy groupxe2x80x9d shown in the formula (I) has the same meaning as the xe2x80x9cC6-14 aromatic hydrocarbon-oxy groupxe2x80x9d in the above definition.
The xe2x80x9c5- to 14-membered heterocycle-oxy groupxe2x80x9d in the xe2x80x9c5- to 14-membered heterocycle-oxy group which may be substitutedxe2x80x9d which is given as the substituent of HAr means a xe2x80x9c5- to 14-membered heterocycle-oxy groupxe2x80x9d corresponding to a ring having the same meaning as the xe2x80x9c5- to 14-membered heterocyclic groupxe2x80x9d and the xe2x80x9c4- to 10-membered non-aromatic heterocyclic groupxe2x80x9d in the aforementioned definition. Specific examples thereof include an xe2x80x9caromatic heterocycle-oxy groupxe2x80x9d such as pyrrolyloxy group, pyridinyloxy group, pyridazinyloxy group, pyrimidinyloxy group, pirazinyloxy group and thiazolyloxy group; and a xe2x80x9cnon-aromatic heterocycle-oxy groupxe2x80x9d such as pyrrolidinyloxy group, pyrrolinyloxy group, piperidinyloxy group, piperazinyloxy group, imidazolinyloxy group, imidazolydinyloxy group, morpholinyloxy group and tetrahydropyranyloxy group. As the xe2x80x9c5- to 14-membered heterocycle-oxy group which may be substitutedxe2x80x9d, a xe2x80x9c5- to 14-membered heterocycle-oxy groupxe2x80x9d which may be substituted with one or more groups selected from (1) hydroxyl group, (2) a halogen atom, (3) nitrile group, (4) a C1-6 alkyl group, C1-6 alkenyl group or C1-6 alkynyl group which may be halogenated, (5) a C1-6 alkoxy group which may be halogenated, (6) a C1-6 alkyl-thio group, C1-6 alkenyl-thio group or C1-6 alkynyl-thio group which may be halogenated, (7) a C1-6 alkoxy-C1-6 alkyl group, (8) acetyl group, (9) a C1-6 alkanoyl group, (10) a mono-(C1-6 hydrocarbon)-amino group, (11) a di-(C1-6 hydrocarbon)-amino group and (12) a tri-(C1-6 hydrocarbon)-amino group is preferable.
The xe2x80x9cC6-14 aromatic hydrocarbon-thio groupxe2x80x9d in the xe2x80x9cC6-14 aromatic hydrocarbon-thio group which maybe substitutedxe2x80x9d given as the substituent of HAr means the xe2x80x9cC1-6 cyclic hydrocarbon-thio groupxe2x80x9d corresponding to the xe2x80x9cC6-14 aromatic hydrocarbon groupxe2x80x9d in the above definition. For example, phenylthio group, pentalenylthio group and naphthylthio group are preferable. As the xe2x80x9cC6-14 aromatic hydrocarbon-thio group which may be substitutedxe2x80x9d, a C6-14 aromatic hydrocarbon-thio groupxe2x80x9d which may be substituted with one or more groups selected from (1) hydroxyl group, (2) a halogen atom, (3) a C1-6 alkyl-sulfonyl group, C1-6 alkenyl-sulfonyl group or C1-6 alkynyl-sulfonyl group which may be halogenated, (4) a C1-4 alkylenedioxy group which may be halogenated, (5) a C1-6 alkoxy group which may be halogenated, (6) a C1-6 hydrocarbon-thio group which may be halogenated, (7) a C1-6 alkoxy-carbonyl group, (8) a C6-14aryl-C1-6 alkoxy group, (9) a C1-7 alkanoylamino group, (10) a C1-6 alkyl-carbamoyl group, (11) a C1-6 alkenyl-carbamoyl group, (12) a C1-6 alkynyl-carbamoyl group and (13) an amino group which may be substituted with a C1-6 hydrocarbon group is preferable.
The xe2x80x9c5- to 14-membered heterocycle-thio group[ in the xe2x80x9c5- to 14-membered heterocycle-thio group which may be substitutedxe2x80x9d which is given as the substituent of HAr means a xe2x80x9c5- to 14-membered heterocycle-thio groupxe2x80x9d corresponding to a ring having the same meaning as the xe2x80x9c5- to 14-membered aromatic heterocyclic groupxe2x80x9d and the xe2x80x9c4- to 10-membered non-aromatic heterocyclic groupxe2x80x9d in the aforementioned definition. Specific examples thereof include an xe2x80x9caromatic heterocycle-thio groupxe2x80x9d such as pyrrolylthio group, pyridinylthio group, pyridazinylthio group, pyrimidinylthio group, pirazinylthio group and thiazolylthio group; and an xe2x80x9cnon-aromatic heterocycle-thio groupxe2x80x9d such as pyrrolidinylthio group, pyrrolinylthio group, piperidinylthio group, piperazinylthio group, imidazolinylthio group, imidazolydinylthio group and morpholinylthio group. Also, as the xe2x80x9c5- to 14-membered heterocycle-thio group which may be substitutedxe2x80x9d, a xe2x80x9c5- to 14-membered heterocycle-thio groupxe2x80x9d which may be substituted with one or more groups selected from (1) hydroxyl group, (2) a halogen atom, (3) nitrile group, (4) a C1-6 alkyl group, C1-6 alkenyl group or C1-6 alkynyl group which may be halogenated, (5) a C1-6 alkoxy group which may be halogenated, (6) a C1-6 alkyl-thio group, C1-6 alkenyl-thio group or C1-6 alkynyl-thio group which may be halogenate (7) a C1-6 alkoxy-C1-6 alkyl group, (8) acetyl group, (9) a C1-6 alkanoyl group, (10) a mono-(C1-6 hydrocarbon)-amino group, (11) a di-(C1-6 hydrocarbon)-amino group and (12) a tri-(C1-6 hydrocarbon)-amino group and (13) an oxo group is preferable. amino group and (3) an oxo group is preferable.
The xe2x80x9camino group which may be substitutedxe2x80x9d given as the substituent of HAr means an amino group represented by the formula xe2x80x94N(R3)R4 (wherein R3 and R4 are the same as or different from each other and each is a group selected from (1) an aromatic heterocyclic group, (2) a non-aromatic heterocyclic group, (3) a C1-6 alkyl group, C1-6 alkenyl group or C1-6 alkynyl group which may be substituted with a halogen atom or a C1-6 alkoxy group, (4) a C3-8 cycloalkyl group, C3-8 cycloalkenyl group or C3-8 cycloalkynyl group which may be halogenated, (5) a carbonyl group which is substituted with a C1-6 alkyl group, C1-6 alkenyl group or C1-6 alkynyl group which may be halogenated, a C3-8 cycloalkyl group, C3-8 cycloalkenyl group or C3-8 cycloalkynyl group which may be halogenated, a C1-6 alkoxy group which may be halogenated, a C6-14 aryl group or an aromatic heterocyclic group, (6) a C1-6 alkanoyl group which may be substituted with a group selected from a C6-14 aryl group and an aromatic heterocyclic group, (7) a carbamoyl group which may be substituted with a C1-6 alkyl group, a C1-6 alkenyl group, a C1-6 alkynyl group, a C6-14 aryl group or an aromatic heterocyclic group and (8) a sulfonyl group which is substituted with a C1-6 alkyl group, a C1-6 alkenyl group or a C1-6 alkynyl group. Also, (9) R3 and R4 may be combined and united to form a 3- to 10-membered ring, and the cyclic amino group may be substituted with one or more groups selected from hydroxyl group, a halogen atom, a C1-6 alkyl group, a C1-6 alkenyl group, a C1-6 alkynyl group, a C1-6 alkoxy group, a C1-6 hydrocarbon-thio group and a C1-4 alkylenedioxy group). An amino group, R3 and R4 are the same as or different from each other and each is a group selected from a C1-6 alkyl group, a C1-6 alkoxy-C1-6 alkyl group, a C1-6 alkoxy-carbonyl group, a C1-6 alkanoyl group, a C6-14 aryl-carbonyl group, a heteroaryl-carbonyl group, a C1-6 alkyl-carbamoyl group, a C6-14 alkyl-carbamoyl group, a C6-14 aryl-sulfonyl group and a 5- to 14-membered heterocyclic group.
Given as example of the xe2x80x9cC1-6 imidoyl groupxe2x80x9d in the xe2x80x9cC1-6 imidoyl group which may be substitutedxe2x80x9d given as the substituent of HAr are formimidoyl, hexaneimidoyl and succinimidoyl. As the xe2x80x9cC1-6 imidoyl group which may be substitutedxe2x80x9d, a C1-6 imidoyl group which may be substituted with a halogen atom is preferable.
Examples of the xe2x80x9csubstituted carbonyl groupxe2x80x9d given as the substituent of HAr include carbonyl groups substituted with a group selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C26 alkynyl group, a C1-6 alkoxy-C1-6 alkyl group, a C1-6 alkoxy group, a C6-4 aryl group and a 5- to 14-membered aromatic heterocyclic group.
The xe2x80x9csubstituted carbonyl groupxe2x80x9d in the xe2x80x9cthe xe2x80x9csubstituted carbonyl-oxy groupxe2x80x9d given as the substituent of HAr is a carbonyl having the same meaning as the xe2x80x9csubstituted carbonyl groupxe2x80x9d in the aforementioned definition. Examples of the xe2x80x9csubstituted carbonyl-oxy groupxe2x80x9d include a C1-6 alkyl-carbonyl-oxy group, a C2-6 alkenyl-carbonyl-oxy group, a C2-6 alkynyl-carbonyl-oxy group, a C1-6 alkoxy-C1-6 alkyl-carbonyl-oxy group, a C1-6 alkoxy-carbonyl-oxy group, a C6-14 aryl-carbonyl-oxy group and 5- to 14-membered aromatic heterocycle-carbonyl-oxy group. Preferable examples are a C1-6 alkyl-carbonyl-oxy group, a C2-6 alkenyl-carbonyl-oxy group and a C2-6 alkynyl-carbonyl-oxy group.
Examples of the xe2x80x9ccarboxyl group which may form a saltxe2x80x9d given as the substituent of HAr include salts of alkali metals such as lithium, sodium and potassium, salts of alkali earth metals such as magnesium and calcium, tetramethylammonium salts, quaternary ammonium salts such as a tetraethylammonium salt, amino acid salts such as alginates, aspartates, glutamate and a proline salt, and further betaines with amino groups in a molecule.
The xe2x80x9ccarbamoyl group which may be substitutedxe2x80x9d given as the substituent of HAr is, specifically, carbamoyl groups represented by the formula xe2x80x94COxe2x80x94N(R5)R6 (wherein R5 and R6 are the same as or different from each other and each represents a group selected from (1) hydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 alkenyl group, (4) a C1-6 alkynyl group, (5) a C3-8 cycloalkyl group, (6) a C3-8 cycloalkenyl group, (7) a C3-8 cycloalkynyl group, (8) a C6-14 aryl group and (9) an aromatic heterocyclic group or (10) R5 and R6 may be combined and united to form a 3- to 8-membered ring). A carbamoyl group, wherein R5 and R6 are the same as or different from each other and each is a group selected from a C1-6 alkynyl group, a C3-8 cycloalkyl group, a C6-14 aryl group which may be halogenated etc., is preferable.
Given as examples of the xe2x80x9cC1-4 alkylenedioxy groupxe2x80x9d in the xe2x80x9cC1-4 alkylenedioxy group which may be substitutedxe2x80x9d given as the substituent of HAr are a methylenedioxy group, ethylenedioxy group and propylenedioxy group. As the xe2x80x9cC1-4 alkylenedioxy group which may be substitutedxe2x80x9d, a C3-4 alkylenedioxy group which may be hydroxylated or halogenated is preferable.
As the xe2x80x9csulfinyl group which may be substitutedxe2x80x9d given as the substituent of HAr, a sulfinyl group which may be substituted with a group selected from (1) a C1-6 hydrocarbon group which may be halogenated and (2) an amino group which may be mono- or di-substituted with a C1-6 hydrocarbon group which may be halogenated is preferable.
As the xe2x80x9csulfonyl group which may be substitutedxe2x80x9d given as the substituent of HAr, a sulfonyl group which may be substituted with a group selected from (1) a C1-6 hydrocarbon group which may be halogenated and (2) an amino group which E may be mono- or di-substituted with a C1-6 hydrocarbon group which may be halogenated is preferable.
The definition of the xe2x80x9caromatic heterocycle which may be substitutedxe2x80x9d represented by HAr in the formula (I) is as above-mentioned. Preferable examples of the substituent of the xe2x80x9caromatic heterocyclexe2x80x9d include (1) a C1-6 alkyl group, C1-6 alkenyl group or C1-6 alkynyl group, which may be substituted with one or two groups selected from (a) hydroxyl group, (b) a halogen atom, (c) a 5- to 14-aromatic heterocyclic group, (d) a 4- to 10-membered non-aromatic heterocyclic group, (e) a 5- to 10-membered condensed heterocyclic group which may be substituted with a C1-6 alkoxy group and (f) a C1-6 alkyl-sulfonyl group, (2) a C1-6 alkoxy group which may be substituted with one or more groups selected from (a) hydroxyl group, (b) a halogen atom, (c) a 4- to 10-membered non-aromatic heterocycle-oxy group, (d) a C1-6 alkoxy group, (e) a C1-6 alkoxy-carbonyl group and (f) a 4- to 10-membered non-aromatic heterocycle, (3) a C6-14 aromatic hydrocarbon cyclic group which may be substituted with one or more groups selected from (a) a halogen atom, (b) a C1-6 alkoxy group and (c) a C1-4 alkylenedioxy group, (4) a 5- to 14-membered aromatic heterocyclic group which may be substituted with one or more groups selected from (a) hydroxyl group, (b) nitrile group, (c) a C1-6 alkyl group, (d) a C1-6 alkoxy group, (e) a C1-6 alkoxy-C1-6 alkyl group, (f) a C1-6 alkanoyl group, (g) a C1-4 alkylenedioxy group, (h) a mono-(C1-6 alkyl)-amino group and (i) a di-(C1-6 alkyl)-amino group and (5) a 4- to 10-membered non-aromatic heterocyclic group which may be substituted with one or more groups selected from (a) hydroxyl group, (b) nitrile group, (c) a C1-6 alkyl group, (d) a C1-6 alkoxy group, (e) a C1-6 alkoxy-C1-6 alkyl group, (f) a C1-6 alkanoyl group, (g) a C1-4 alkylenedioxy group, (h) a mono-(C1-6 alkyl)-amino group and (i) a di-(C1-6 alkyl)-amino group. More preferable examples include a C1-6 alkyl group which may be halogenated, a C2-6 alkenyl group which may be halogenated, a C1-6 alkoxy-C1-6 alkyl group, a C1-6 alkyl group substituted with a C6-14 aromatic hydrocarbon cyclic group, a C1-6 alkyl group substituted with 5- or 6-membered aromatic heterocycle, a C1-6 alkoxy group which may be halogenated, a C1-6 alkoxy-C1-6 alkoxy group, a C6-14 aromatic hydrocarbon group, a 5- or 6-membered aromatic heterocycle which may be substituted with a C1-6 alkyl group and a 4- to 10-membered non-aromatic heterocyclic group which may be substituted with one or more groups selected from (a) hydroxyl group, (b) nitrile group and (c) a C1-6 alkoxy group.
The terms xe2x80x9chalogen atomxe2x80x9d, xe2x80x9cC1-6 hydrocarbon groupxe2x80x9d, xe2x80x9cC1-6 alkyl groupxe2x80x9d, xe2x80x9cC3-8 alkenyl groupxe2x80x9d, xe2x80x9cC3-8 alkynyl groupxe2x80x9d, xe2x80x9cC3-8 cycloalkyl groupxe2x80x9d, xe2x80x9cC3-8 cycloalkenyl groupxe2x80x9d, xe2x80x9cC3-8 cycloalkynyl groupxe2x80x9d, xe2x80x9cC6-14 aromatic hydrocarbon groupxe2x80x9d, C6-14 aryl groupxe2x80x9d, xe2x80x9c5- to 14-membered aromatic heterocyclic groupxe2x80x9d, xe2x80x9c5- to 14-membered heteroaryl groupxe2x80x9d, xe2x80x9c4- to 10-membered non-aromatic heterocyclic groupxe2x80x9d, xe2x80x9cC1-6 alkoxy groupxe2x80x9d, xe2x80x9cC3-8 cycloalkoxy groupxe2x80x9d, xe2x80x9cC3-8 cycloalkyloxy groupxe2x80x9d, xe2x80x9cC3-8 cycloalkenyloxy groupxe2x80x9d, xe2x80x9cC1-6 hydrocarbon-thio groupxe2x80x9d, xe2x80x9cC1-6 alkylthio groupxe2x80x9d, xe2x80x9cC1-6 alkenylthio groupxe2x80x9d, xe2x80x9cC1-6 alkynylthio groupxe2x80x9d, xe2x80x9cC3-8 cycloalkylthio groupxe2x80x9d, xe2x80x9cC3-8 cycloalkenylthio groupxe2x80x9d, xe2x80x9cC1-6 alkoxy-carbonyl groupxe2x80x9d, xe2x80x9cC1-6 alkanoyl groupxe2x80x9d, xe2x80x9cC1-6 alkanoyloxy groupxe2x80x9d, xe2x80x9ccarbamoyl groupxe2x80x9d, xe2x80x9cC1-6 imidoyl groupxe2x80x9d, xe2x80x9ccarboxyl group which may form a saltxe2x80x9d, xe2x80x9cC1-4 alkylenedioxy groupxe2x80x9d, xe2x80x9csulfonyl groupxe2x80x9d and xe2x80x9csulfinyl groupxe2x80x9d, which are all used in the above-mentioned definitions concerning the substituents of the aromatic heterocycle HAr have the same meanings as defined above.
In the specification of the present invention, the xe2x80x9caromatic ringxe2x80x9d in the xe2x80x9caromatic ring which may be substitutedxe2x80x9d represented by Ar in the formula (I) means a ring having the same meaning as the xe2x80x9caromatic ringxe2x80x9d in the above definition. For example, benzene ring, a pyridine ring and the like are preferable. Examples of the xe2x80x9caromatic ring which may be substitutedxe2x80x9d include aromatic rings which may be substituted with one or more groups selected from (1) hydroxyl group, (2) a halogen atom, (3) a C1-6 chain hydrocarbon group which may be substituted, (4) a C3-8 cyclic hydrocarbon group which may be substituted, (5) a C1-6 alkoxy group which may be substituted, (6) a C3-8 cycloalkoxy group which may be substituted, (7) a C1-6 chain hydrocarbon-thio group which may be substituted, (8) a C3-8 cyclic hydrocarbon-thio group, (9) a C6-14 aromatic hydrocarbon cyclic group which may be substituted, (10) a 5- to 14-membered heterocyclic group which may be substituted, (11) an amino group which may be substituted with a C1-6 alkyl group and (12) a C1-4 alkylenedioxy group which may be substituted.
The xe2x80x9cC1-6 chain hydrocarbon group which may be substitutedxe2x80x9d given as the substituent of Ar means a group having the same meaning as the xe2x80x9cC1-6 chain hydrocarbon group which may be substitutedxe2x80x9d shown in the definition of HAr. As the xe2x80x9cC1-6 chain hydrocarbon group which may be substitutedxe2x80x9d, a C1-6 alkyl group which may be halogenated, a C1-6 alkenyl group which may be halogenated, a C1-6 alkynyl group which may be halogenated and the like are preferable.
The xe2x80x9cC3-8 cyclic hydrocarbon group which may be substitutedxe2x80x9d given as the substituent of Ar means a group having the same meaning as the xe2x80x9cC3-8 cyclic hydrocarbon group which may be substitutedxe2x80x9d shown in the definition of HAr. As the xe2x80x9cC3-8 cyclic hydrocarbon group which may be substitutedxe2x80x9d, a C3-8 cycloalkyl group which may be halogenated, a C3-8 cycloalkenyl group which may be halogenated and the like are preferable.
The xe2x80x9cC1-6 alkoxy group which may be substitutedxe2x80x9d given as the substituent of Ar means a group having the same meaning as the xe2x80x9cC1-6 alkoxy group which may be substitutedxe2x80x9d shown in the definition of HAr. As the xe2x80x9cC1-6 alkoxy group which may be substitutedxe2x80x9d, a C1-6 alkoxy group which may be halogenated and the like are preferable.
The xe2x80x9cC1-6 cycloalkoxy group which may be substitutedxe2x80x9d given as the substituent of Ar means a group having the same meaning as the xe2x80x9cC3-8 cycloalkoxy group which may be substitutedxe2x80x9d shown in the definition of HAr. As the xe2x80x9cC3-8 cycloalkoxy group which may be substitutedxe2x80x9d, a C3-8 cycloalkyloxy group which may be halogenated, a C3-8 cycloalkenyloxy group which may be halogenated and the like are preferable.
The xe2x80x9cC1-6 chain hydrocarbon-thio group which may be substitutedxe2x80x9d given as the substituent of Ar means a group having the same meaning as the xe2x80x9cC1-6 chain hydrocarbon-thio group which may be substitutedxe2x80x9d shown in the definition of HAr. As the xe2x80x9cC1-6 chain hydrocarbon-thio group which may be substitutedxe2x80x9d, a C1-6 alkyl-thio group which may be halogenated, a C1-6 alkenyl-thio group which may be halogenated, a C1-6 alkynyl-thio group which may be halogenated and the like are preferable.
The xe2x80x9cC3-8 cyclic hydrocarbon-thio groupxe2x80x9d given as the substituent of Ar means a group having the same meaning as the xe2x80x9cC3-8 cyclic hydrocarbon-thio group which may be substitutedxe2x80x9d shown in the definition of HAr. As the xe2x80x9cC3-8 cyclic hydrocarbon-thio group which may be substitutedxe2x80x9d, a C3-8 cycloalkylthio group which may be halogenated, a C3-8 cycloalkenylthio group which may be halogenated and the like are preferable.
The xe2x80x9cC6-14 aromatic hydrocarbon cyclic group which may be substitutedxe2x80x9d and xe2x80x9c5- to 14-membered heterocyclic group which may be substitutedxe2x80x9d which are given as the substituents of Ar mean groups having the same meanings as the xe2x80x9cC6-14 aromatic hydrocarbon cyclic group which may be substitutedxe2x80x9d and the xe2x80x9c5- to 14-membered heterocyclic group which may be substitutedxe2x80x9d shown in the definitions of HAr respectively.
The xe2x80x9camino group which may be substituted with a C1-6 alkyl groupxe2x80x9d given as the substituent of Ar means an amino group mono-substituted with a C1-6 alkyl group such as methylamino group and ethylamino group and an amino group di-substituted with a C1-6 alkyl group such as dimethylamino group and diethylamino group. Further, the nitrogen atom may be tri-substituted with a C1-6 alkyl group to form an ammonium salt.
The xe2x80x9cC1-4 alkylenedioxy group which may be substitutedxe2x80x9d given as the substituent of Ar means a group having the same meaning as the xe2x80x9cC1-4 alkylenedioxy group which may be substitutedxe2x80x9d shown in the definition of HAr. For example, a C1-4 alkylenedioxy group which may be substituted with a halogen atom etc. is preferable.
As above-mentioned, the xe2x80x9caromatic ring which may be substitutedxe2x80x9d represented by Ar in the formula (I) is defined. Preferable examples of Ar include a benzene ring, pyridine ring, pyrazine ring, thiophene ring and thiazole ring, which maybe substituted with a group selected from hydroxyl group, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group and the like.
In the specification of the present invention, W in the formula (I) means a connecting chain in which the primary chain is constituted of two or more atoms. Examples thereof include preferably a chain represented by (1) xe2x80x94CH2xe2x80x94CH2xe2x80x94 which may be substituted, (2) xe2x80x94CHxe2x95x90CHxe2x80x94 which may be substituted, (3) xe2x80x94Cxe2x89xa1Cxe2x80x94, (4) xe2x80x94NHxe2x80x94COxe2x80x94, (5) xe2x80x94COxe2x80x94NHxe2x80x94, (6) xe2x80x94NHxe2x80x94CH2xe2x80x94, (7) xe2x80x94CH2xe2x80x94NHxe2x80x94, (8) xe2x80x94CH2xe2x80x94COxe2x80x94, (9) xe2x80x94COxe2x80x94CH2xe2x80x94, (10) xe2x80x94NHxe2x80x94S(O)1xe2x80x94, (11) xe2x80x94S(O)1xe2x80x94NHxe2x80x94, (12) xe2x80x94CH2xe2x80x94S(O)1xe2x80x94 and (13) xe2x80x94S(O)1xe2x80x94CH2xe2x80x94 (1 denotes 0, 1 or 2), more preferably (1) xe2x80x94CH2xe2x80x94CH2xe2x80x94, (2) xe2x80x94CHxe2x95x90CHxe2x80x94 and (3) xe2x80x94C57 Cxe2x80x94, and further preferably xe2x80x94Cxe2x89xa1Cxe2x80x94.
In the specification of the present invention, examples of the connecting group X in the formula (I) include chains represented by (1) a single bond, (2) a C1-6 alkylene chain which may be substituted, (3) a C2-6 alkenylene chain which may be substituted, (4) a C2-6 alkynylene chain which may be substituted, (5) a formula xe2x80x94Qxe2x80x94 (wherein Q represents oxygen atom, sulfur atom, CO or N(R) (wherein R represents a C1-6 alkyl group or a C1-6 alkoxy group)), (6) xe2x80x94NHxe2x80x94COxe2x80x94, (7) xe2x80x94COxe2x80x94NHxe2x80x94, (8) xe2x80x94NHxe2x80x94CH2xe2x80x94, (9) xe2x80x94CH2xe2x80x94NHxe2x80x94, (10) xe2x80x94CH2xe2x80x94COxe2x80x94, (11) xe2x80x94COxe2x80x94CH2xe2x80x94, (12) xe2x80x94NHxe2x80x94S(O)mxe2x80x94, (13) xe2x80x94S(O)mxe2x80x94NHxe2x80x94, (14) xe2x80x94CH2xe2x80x94S(O)mxe2x80x94, (15) xe2x80x94S(O)mxe2x80x94CH2xe2x80x94 (wherein m denotes 0, 1 or 2) or (16) xe2x80x94(CH2)nxe2x80x94Oxe2x80x94 (wherein n denotes an integer from 1 to 6). Here, the xe2x80x9cC1-6 alkylene chainxe2x80x9d, the xe2x80x9cC1-6 alkenylene chainxe2x80x9d and the xe2x80x9cC1-6 alkynylene chainxe2x80x9d mean chains corresponding to C1-6 hydrocarbon groups having the same meanings as the xe2x80x9cC1-6 alkyl groupxe2x80x9d, the xe2x80x9cC1-6 alkenyl groupxe2x80x9d and the xe2x80x9cC1-6 alkynyl groupxe2x80x9d in the above definitions. The connecting chain X represents preferably a single bond, a C1-6 alkylene chain, a C2-6 alkynylene chain, xe2x80x94COxe2x80x94 or the like and more preferably a simple bond, methylene chain, ethylene chain or xe2x80x94COxe2x80x94.
The amino group in the xe2x80x9camino group which may be substituted with a C1-6 alkyl group or an acyl groupxe2x80x9d means an amino group which may be substituted with a C1-6 alkyl group having the same meaning as the aforementioned definition or an acyl group having the same meaning as the above definition. Specific examples thereof include an N-formylamino group, N-acetylamino group, N-propionylamino group, N-pivaloylamino group, N-benzoylamino group, N-methyl-N-formylamino group, N-methyl-N-benzoylamino group, N-methylamino group, N,N-dimethylamino group, N-methyl-N-ethylamino group, N-(n-propyl)amino group, N-(i-propyl)amino group and N-(t-butyl)amino group.
The xe2x80x9cC1-6 alkoxycarbonyl groupxe2x80x9d is an alkoxycarbonyl group corresponding to the C1-6 alkoxy group in the above definition. Specific examples thereof include methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, i-propoxycarbonyl group, sec-propoxycarbonyl group, n-butoxycarbonyl group, i-butoxycarbonyl group, 1,2-dimethylpropoxycarbonyl group and 2-ethylpropoxycarbonyl group.
The definitions of R1, HAr, Ar, W and X to be used in the formula (I) have been described as above. To state more preferable examples, as examples of xe2x80x94Xxe2x80x94Ar, a benzyl group (X=methylene chain; Ar=benzene ring) which may be substituted is given and as examples of HAr, besides a substituent xe2x80x94Xxe2x80x94Ar, a pyridine ring, pyrimidine ring, pyridazine ring, pyrazine ring, indole ring, quinoline ring, thiophene ring or benzothiophene ring which may be substituted with one or two groups selected from (1) a 5- or 6-membered aromatic heterocycle which may be substituted with a C1-6 alkyl group, (2) a 5- or 6-membered non-aromatic heterocycle which may be substituted one or more groups selected from (a) hydroxyl group, (b) a C1-6 alkyl group and (c) a C1-6 alkoxy group, (3) a C6-10 aromatic hydrocarbon ring which may be substituted with one or more groups selected from (a) a halogen atom, (b) a C1-6 alkoxy group, (c) a C1-4 alkylenedioxy group and (d) a sulfonyl group which may be substituted with a C1-6 alkyl group, (4) a C1-6 alkyl group which may be substituted with one or two groups selected from (a) hydroxyl group, (b) a halogen atom, (c) a 5- or 6-membered aromatic heterocycle and (d) a C1-6 alkoxy group and (5) a C1-6 alkoxy group which may be substituted with (a) a halogen atom and (b) a C1-6 alkoxy group. More preferable examples of HAr include a pyridine ring, pyrimidine ring, pyridazine ring, pyrazine ring, indole ring, quinoline ring, thiophene ring or benzothiophene ring which may be substituted with one or two groups selected from (1) a benzene ring which may be substituted with a C1-4 alkylenedioxy group, (2) pyridine ring, (3) pyrimidine ring, (4) pyridazine ring, (5) pyrazine ring, (6) thiophene ring, (7) a piperidine ring which may be substituted with a C1-6 alkoxy group, (8) a piperazine ring which may be substituted with a C1-6 alkoxy group, (9) a pyrrolidine ring which may be substituted with a C1-6 alkoxy group, (10) a piperidine ring substituted with hydroxyl group and a C1-6 alkoxy group, (11) a piperazine ring substituted with hydroxyl group and a C1-6 alkoxy group, (12) a pyrrolidine ring substituted with hydroxyl group and a C1-6 alkoxy group, (13) morpholine ring, (14) a C1-6 alkyl group which may be substituted with a C1-6 alkoxy group and (15) a C1-6 alkoxy group which may be substituted with hydroxyl group or a C1-6 alkoxy group.
The salts in the present invention mean generally pharmacologically acceptable salts. Examples of these salts include hydrohalides such as hydrofluorides, hydrochlorides, hydrobromides and hydroiodides; inorganic acid salts such as sulfates, nitrates, perchlorates, phosphates, carbonates and bicarbonates; organic carboxylates such as acetates, maleates, tartrates and fumarates; organic sulfonates such as methanesulfonates, trifluoromethanesulfonates, ethanesulfonates, benzene sulfonates and toluene sulfonates; amino acid salts such as alginates, aspartates and glutamates; salts with amines such as trimethylamine salts, triethylamine salts, procaine salts, pyridium salts and phenethylbenzylamine salts; alkali metal salts such as sodium salts and potassium salts; and alkali earth metal salts such as magnesium salts and calcium salts.
Various methods are considered as a method for producing the compound represented by the formula (I) according to the present invention and the compound can be produced by a usual organic synthetic method. To state a typical method, for example, the following method may be used to produce the compound. 
The above production method is a method of producing the compound (IV) according to the invention of the patent application of this case by coupling the aromatic heterocyclic compounds (II) and (III) with each other. In the formula, A1, A2 and A3 are the same as or different form each other and each means (1) a carbon atom which may be substituted or (2) a heteroatom such as nitrogen atom, sulfur atom or oxygen atom, wherein there is the case where A2 further means a single bond. When A2 means a single bond, the ring to which A1, A2 and A3 belong is a 5-membered ring. Here, in the case where A1, A2 and A3 respectively represent the xe2x80x9ccarbon atom which may be substitutedxe2x80x9d, the term xe2x80x9cmay be substitutedxe2x80x9d means that it may be substituted with the substituent shown in HAr defined above. Specifically, the carbon atom may be substituted with a group selected from (1) halogen atom, (2) hydroxyl group, (3) thiol group, (4) nitro group, (5) nitrile group, (6) a C1-6 chain hydrocarbon group which may be substituted, (7) a C3-8 cyclic hydrocarbon group which may be substituted, (8) a C6-14 aromatic hydrocarbon cyclic group which may be substituted, (9) a 5- to 14-membered aromatic heterocyclic group which may be substituted, (10) a 4- to 10-membered non-aromatic heterocyclic group which may be substituted, (11) a C1-6 alkoxy group which may be substituted, (12) a C3-8 cycloalkyloxy group which may be substituted, (13) a C1-6 chain hydrocarbon-thio group which may be substituted, (14) a C3-8 cyclic hydrocarbon-thio group which may be substituted, (15) a C6-4 aromatic hydrocarbon-oxy group which may be substituted, (16) a 5- to 14-membered heterocycle-oxy group which may be substituted, (17) a C6-14 aromatic hydrocarbon-thio group which may be substituted, (18) a 5- to 14-membered heterocycle-thio group which may be substituted, (19) an amino group which may be substituted, (20) azide group, (21) guanidino group, (22) carbamide group, (23) formyl group, (24) a C1-6 imidoyl group which may be substituted, (25) a carbonyl group which is substituted, (26) a carbonyl-oxy group which is substituted, (27) a carboxyl group which may form a salt, (28) a carbamoyl group which may be substituted, (29) a C1-4 alkylenedioxy group which may be substituted, (30) a sulfinyl group which may be substituted and (31) a sulfonyl group which may be substituted. * L means a leaving group and R1 means hydrogen atom or hydroxyl group, a and b respectively mean a group xe2x80x94Xxe2x80x94Ar (wherein X and Ar have the same meaning as defined above) and the substituent of HAr of the formula (I) described in the aforementioned definition, or respectively mean the substituent of HAr and group xe2x80x94Xxe2x80x94Ar (wherein X and Ar have the same meaning as defined above) of the formula (I) described in the above definition. The leaving group L may be any group so long as it is known as a leaving group in organic synthesis and no particular limitation is imposed. Examples thereof include halogen atoms such as chlorine atom, bromine atom and iodine atom; substituted or unsubstituted acetoxy groups such as acetoxy group and trifluoroacetoxy group; substituted sulfonyloxy groups such as methanesulfonyloxy group trifluoromethanesulfonyloxy group, benzenesulfonyloxy group and p-toluenesulfonyloxy group; and substituted phosphoryloxy groups such as diphenoxyphosphoryloxy. Among these groups, halogen atoms such as chlorine atom, bromine atom and iodine atom and trifluoromethanesulfonyloxy group are preferable. As the palladium catalyst, for example, tetrakis(triphenylphosphine)palladium(0) or bis(triphenylphosphine)palladium(II) chloride may be used in an amount of 0.00001 to 0.1 mol equivalents. For example, 0.0001 to 0.1 mol equivalents of cuprous iodide or cuprous chloride may be used as the copper salt and for example, 1 to 5 equivalents of triethyl amine or N,N-diisopropylethylamine may be used as the base. As the solvent, N,N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, methanol or a mixture of these solvents is used. The reaction temperature is preferably 0xc2x0 C. to 140xc2x0 C. 
The above production methods ensure that the compounds (VI) and (VIII) according to the present invention may be produced. In the reaction formula, L and a have the same meanings as those in the above definition. As L, for example, chlorine atom, bromine atom, iodine atom or trifluoromethanesulfonyloxy group may be used. M means a metal atom which may have a substituent. For example, trinbutyltin or dihydroxyboron is preferable. As the palladium catalyst, for example, tetrakis triphenylphosphine)palladium(0) or bis(triphenylphosphine)palladium(II) chloride may be used in an amount of 0.0001 to 0.1 mol equivalents. Examples of the solvent include toluene, xylene, N,N-dimethylformamide and N-methylpyrrolidone. A reaction temperature ranging from 50xc2x0 C. to 150xc2x0 C. is adopted. When the metal M is boron, an inorganic base such as sodium carbonate or an organic base such as triethylamine is used as the base. As the solvent, an organic solvent containing water is also used.
No particular limitation is imposed on the dosage form of the compound according to the present invention and either oral administration or parenteral administration according to a method which is usually used is acceptable. The compound may be made into preparations of a tablet, powder, granule, capsule agent, syrup agent, troche, inhalant, suppository, injection, ointment, ophthalmic ointment, ophthalmic solution, collunarium, ear drop, cataplasm and lotion, and administered. In the preparation of these forms, fillers, binders, lubricants, colorants, flavoring agents, and if necessary, stabilizers, emulsifiers, absorbefacient agents, surfactants, pH regulators, antiseptics and antioxidants etc. may be used and components which are usually used as raw materials of medicinal preparations are formulated to prepare a medicine by a usual method. Examples of these components include animal or vegetable oils such as soybean oil, beef tallow and synthetic glyceride; hydrocarbons such as liquid paraffin, squalane and solid paraffin; ester oils such as octyldodecyl myristate and isopropyl myristate; higher alcohols such as cetostearyl alcohol and behenyl alcohol; silicon resins; silicon oils; surfactants such as polyoxyethylene fatty acid ester, sorbitan fatty acid ester, glycerol fatty acid ester, polyoxyethylenesorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil and polyoxyethylene/polyoxypropylene block copolymers; water-soluble polymers such as hydroxyethyl cellulose, polyacrylic acid, carboxyvinyl polymers, polyethylene glycol, polyvinylpyrrolidone and methyl cellulose; lower alcohols such as ethanol and isopropanol; polyhydric. alcohols such as glycerol, propylene glycol, dipropylene glycol and sorbitol; sugars such as glucose and cane sugar; inorganic powders such as silicic acid anhydride, aluminum magnesium silicate and aluminum silicate; and purified water.
The medicine according to the present invention is administered to an adult patient at a dose of generally about 30 xcexcg to 10 g, preferably 100 xcexcg to 5 g and more preferably 100 xcexcg to 100 mg in the case of oral administration and about 30 xcexcg to 1 g, preferably 100 xcexcg to 500 mg and more preferably 100 xcexcg to 30 mg in the case of injection in one to several parts a day although the dose differs depending on the degree of a symptom, age, sex, weight, dosage form and type of disease.